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https://www.readbyqxmd.com/read/29352507/nuclear-and-membrane-estrogen-receptor-antagonists-induce-similar-mtorc2-activation-reversible-changes-in-synaptic-protein-expression-and-actin-polymerization-in-the-mouse-hippocampus
#1
Fang-Zhou Xing, Yan-Gang Zhao, Yuan-Yuan Zhang, Li He, Ji-Kai Zhao, Meng-Ying Liu, Yan Liu, Ji-Qiang Zhang
AIMS: Estrogens play pivotal roles in hippocampal synaptic plasticity through nuclear receptors (nERs; including ERα and ERβ) and the membrane receptor (mER; also called GPR30), but the underlying mechanism and the contributions of nERs and mER remain unclear. Mammalian target of rapamycin complex 2 (mTORC2) is involved in actin cytoskeleton polymerization and long-term memory, but whether mTORC2 is involved in the regulation of hippocampal synaptic plasticity by ERs is unclear. METHODS: We treated animals with nER antagonists (MPP/PHTPP) or the mER antagonist (G15) alone or in combination with A-443654, an activator of mTORC2...
January 19, 2018: CNS Neuroscience & Therapeutics
https://www.readbyqxmd.com/read/29351204/mtor-cross-talk-in-cancer-and-potential-for-combination-therapy
#2
REVIEW
Fabiana Conciatori, Ludovica Ciuffreda, Chiara Bazzichetto, Italia Falcone, Sara Pilotto, Emilio Bria, Francesco Cognetti, Michele Milella
The mammalian Target of Rapamycin (mTOR) pathway plays an essential role in sensing and integrating a variety of exogenous cues to regulate cellular growth and metabolism, in both physiological and pathological conditions. mTOR functions through two functionally and structurally distinct multi-component complexes, mTORC1 and mTORC2, which interact with each other and with several elements of other signaling pathways. In the past few years, many new insights into mTOR function and regulation have been gained and extensive genetic and pharmacological studies in mice have enhanced our understanding of how mTOR dysfunction contributes to several diseases, including cancer...
January 19, 2018: Cancers
https://www.readbyqxmd.com/read/29344639/therapeutic-potential-of-a-dual-mtorc1-2-inhibitor-for-the-prevention-of-posterior-capsule-opacification-an-in-vitro-study
#3
Hao Feng, Zhibo Yang, Xue Bai, Meirong Yang, Yuan Fang, Xiaonan Zhang, Qiqiang Guo, Hong Ning
Mammalian target of rapamycin (mTOR) serves a central role in regulating cell growth and survival, and has been demonstrated to be involved in the pathological progression of posterior capsule opacification (PCO). In the present study, the potency of PP242, a novel dual inhibitor of mTOR complex 1/2 (mTORC1/2), in the suppression of the growth of human lens epithelial cells (HLECs) was investigated. Using a Cell Counting Kit‑8 and a wound healing assay, it was demonstrated that PP242 inhibited the proliferation and migration of HLECs...
January 18, 2018: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29337437/canonical-signaling-and-nuclear-activity-of-mtor-a-teamwork-effort-to-regulate-metabolism-and-cell-growth
#4
REVIEW
Vincent Giguère
Mechanistic (or mammalian) target of rapamycin (mTOR) is a kinase that regulates almost all functions related to cell growth and metabolism in response to extra- and intracellular stimuli such as availability of nutrients, presence of growth factors or the energy status of the cell. As part of two distinct protein complexes, mTORC1 and mTORC2, the kinase has been shown to influence cell growth and proliferation by controlling ribosome biogenesis, mRNA translation, carbohydrate and lipid metabolism, protein degradation, autophagy as well as microtubule and actin dynamics...
January 16, 2018: FEBS Journal
https://www.readbyqxmd.com/read/29331082/mechanistic-target-of-rapamycin-complex-1-and-2-in-human-temporal-lobe-epilepsy
#5
Delia M Talos, Leah M Jacobs, Sarah Gourmaud, Carlos A Coto, Hongyu Sun, Kuei-Cheng Lim, Timothy H Lucas, Kathryn A Davis, Maria Martinez-Lage, Frances E Jensen
OBJECTIVE: Temporal lobe epilepsy (TLE) is a chronic epilepsy syndrome defined by seizures and progressive neurological disabilities, including cognitive impairments, anxiety and depression. Here, human TLE specimens were investigated focusing on the mechanistic target of rapamycin (mTOR) Complex 1 (mTORC1) and Complex 2 (mTORC2) activities in the brain, as both pathways may represent unique targets for treatment. METHODS: Surgically resected hippocampal and temporal lobe samples from therapy-resistant TLE patients were analyzed by Western blotting to quantify the expression of established mTORC1 and mTORC2 activity markers and upstream or downstream signaling pathways involving the two complexes...
January 13, 2018: Annals of Neurology
https://www.readbyqxmd.com/read/29330505/over-expression-of-a-retinol-dehydrogenase-srp35-dhrs7c-in-skeletal-muscle-activates-mtorc2-enhances-glucose-metabolism-and-muscle-performance
#6
Alexis Ruiz, Erez Dror, Christoph Handschin, Regula Furrer, Joaquin Perez-Schindler, Christoph Bachmann, Susan Treves, Francesco Zorzato
SRP-35 is a short-chain dehydrogenase/reductase belonging to the DHRS7C dehydrogenase/ reductase family 7. Here we show that its over-expression in mouse skeletal muscles induces enhanced muscle performance in vivo, which is not related to alterations in excitation-contraction coupling but rather linked to enhanced glucose metabolism. Over-expression of SRP-35 causes increased phosphorylation of AktS473, triggering plasmalemmal targeting of GLUT4 and higher glucose uptake into muscles. SRP-35 signaling involves RARα and RARγ (non-genomic effect), PI3K and mTORC2...
January 12, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29303510/loss-of-pten-synergizes-with-c-met-to-promote-hepatocellular-carcinoma-development-via-mtorc2-pathway
#7
Zhong Xu, Junjie Hu, Hui Cao, Maria G Pilo, Antonio Cigliano, Zixuan Shao, Meng Xu, Silvia Ribback, Frank Dombrowski, Diego F Calvisi, Xin Chen
Hepatocellular carcinoma (HCC) is a deadly malignancy with limited treatment options. Activation of the AKT/mTOR cascade is one of the most frequent events along hepatocarcinogenesis. mTOR is a serine/threonine kinase and presents in two distinct complexes: mTORC1 and mTORC2. While mTORC1 has been extensively studied in HCC, the functional contribution of mTORC2 during hepatocarcinogenesis has not been well characterized, especially in vivo. Pten expression is one of the major mechanisms leading to the aberrant activation of the AKT/mTOR signaling...
January 5, 2018: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/29251327/survival-pathway-of-cholangiocarcinoma-via-akt-mtor-signaling-to-escape-raf-mek-erk-pathway-inhibition-by-sorafenib
#8
Kenta Yokoi, Akira Kobayashi, Hiroaki Motoyama, Masato Kitazawa, Akira Shimizu, Tsuyoshi Notake, Takahide Yokoyama, Tomio Matsumura, Michiko Takeoka, Shin-Ichi Miyagawa
Cholangiocarcinoma (CCC) is a strongly aggressive malignancy for which surgical resection is the only potential curative therapy. Sorafenib, a multikinase inhibitor of the RAF/MEK/ERK pathway, is a molecular-targeted drug that is approved for hepatocellular carcinoma (HCC) but not for CCC. The differences in signaling pathway characteristics under sorafenib treatment between HCC (HLF, Huh7, PLC/PRF/5) and CCC (RBE, YSCCC, Huh28) cell lines were therefore investigated using cell proliferation, western blotting, and apoptosis analyses...
February 2018: Oncology Reports
https://www.readbyqxmd.com/read/29246543/oncostatin-m-upregulates-hif-1%C3%AE-in-breast-tumor-associated-macrophages-independent-of-intracellular-oxygen-concentration
#9
Richa Shrivastava, Varsha Singh, Mohammad Asif, Mahendra Pal Singh Negi, Smrati Bhadauria
AIMS: HIF is an important transcription-regulator for adaptation to cellular stress in cells of myeloid origin. Classically, expression and activity of HIF1-α is regulated by oxygen-concentration within cell. However, there exists an alternative regulatory mechanism affecting HIF1-α levels independent of oxygen concentration particularly in inflammatory cells like macrophages. Here we report the mechanism of HIF1-α upregulation in TAMs by Oncostatin-M (OSM) independent of cellular oxygen concentration...
December 12, 2017: Life Sciences
https://www.readbyqxmd.com/read/29245915/curcumin-interacts-with-sildenafil-to-kill-gi-tumor-cells-via-endoplasmic-reticulum-stress-and-reactive-oxygen-nitrogen-species
#10
Jane L Roberts, Andrew Poklepovic, Laurence Booth
The present studies focused on the ability of the phosphodiesterase 5 (PDE5) inhibitor sildenafil to enhance the anti-cancer properties of clinically relevant concentrations of the dietary diarylheptanoid curcumin. In gastrointestinal tumor cells, sildenafil and curcumin interacted in a greater than additive fashion to kill. Inhibition of the extrinsic apoptotic pathway suppressed killing by ∼50%, as did blockade of the intrinsic apoptotic pathway. Sildenafil and curcumin reduced mTORC1 and mTORC2 activity and increased Beclin1 levels and the numbers of autophagosomes and autolysosomes in cells in a PERK-eIF2α-dependent fashion...
November 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/29242283/phase-ii-study-of-bez235-versus-everolimus-in-patients-with-mammalian-target-of-rapamycin-inhibitor-na%C3%A3-ve-advanced-pancreatic-neuroendocrine-tumors
#11
Ramon Salazar, Rocio Garcia-Carbonero, Steven K Libutti, Andrew E Hendifar, Ana Custodio, Rosine Guimbaud, Catherine Lombard-Bohas, Sergio Ricci, Heinz-Josef Klümpen, Jaume Capdevila, Nicholas Reed, Annemiek Walenkamp, Enrique Grande, Sufiya Safina, Tim Meyer, Oliver Kong, Herve Salomon, Ranjana Tavorath, James C Yao
LESSONS LEARNED: Treatment with BEZ235 has not been shown to demonstrate increased efficacy compared with everolimus and may be associated with a poorer tolerability profile.The hypothesis of dual targeting of the phosphatidylinositol 3-kinase and mammalian target of rapamycin pathways in patients with advanced pancreatic neuroendocrine tumors may warrant further study using other agents. BACKGROUND: This phase II study investigated whether targeting the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway via PI3K, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) inhibition using BEZ235 may be more effective than mTORC1 inhibition with everolimus in patients with advanced pancreatic neuroendocrine tumors (pNET) who are naïve to mTOR inhibitor therapy...
December 14, 2017: Oncologist
https://www.readbyqxmd.com/read/29234390/astragaloside-iv-ameliorates-airway-inflammation-in-an-established-murine-model-of-asthma-by-inhibiting-the-mtorc1-signaling-pathway
#12
Hualiang Jin, Limin Wang, Bei Li, Cui Cai, Jian Ye, Junbo Xia, Shenglin Ma
Astragaloside IV (AS-IV), a main active constituent of Astragalus membranaceus, has been confirmed to have antiasthmatic effects. However, it remained unclear whether the beneficial effects of AS-IV on asthma were attributed to the mTOR inhibition; this issue was the focus of the present work. BALB/c mice were sensitized and challenged with ovalbumin followed with 3 weeks of rest/recovery and then reexposure to ovalbumin. AS-IV was administrated during the time of rest and reexposure. The characteristic features of allergic asthma, including airway hyperreactivity, histopathology, cytokines (IL-4, IL-5, IL-13, IL-17, and INF-γ), and CD4+CD25+Foxp3+Treg cells in bronchoalveolar lavage fluid (BALF), and downstream proteins of mTORC1/2 signaling were examined...
2017: Evidence-based Complementary and Alternative Medicine: ECAM
https://www.readbyqxmd.com/read/29232655/towards-specific-inhibition-of-mtorc2
#13
Elizabeth R Murray, Angus J M Cameron
No abstract text is available yet for this article.
December 12, 2017: Aging
https://www.readbyqxmd.com/read/29232555/mtorc2-promotes-tumorigenesis-via-lipid-synthesis
#14
Yakir Guri, Marco Colombi, Eva Dazert, Sravanth K Hindupur, Jason Roszik, Suzette Moes, Paul Jenoe, Markus H Heim, Isabelle Riezman, Howard Riezman, Michael N Hall
Dysregulated mammalian target of rapamycin (mTOR) promotes cancer, but underlying mechanisms are poorly understood. We describe an mTOR-driven mouse model that displays hepatosteatosis progressing to hepatocellular carcinoma (HCC). Longitudinal proteomic, lipidomics, and metabolomic analyses revealed that hepatic mTORC2 promotes de novo fatty acid and lipid synthesis, leading to steatosis and tumor development. In particular, mTORC2 stimulated sphingolipid (glucosylceramide) and glycerophospholipid (cardiolipin) synthesis...
December 11, 2017: Cancer Cell
https://www.readbyqxmd.com/read/29207163/preclinical-analysis-of-mtor-complex-1-2-inhibition-in-diffuse-intrinsic-pontine-glioma
#15
Patrick C Flannery, John A DeSisto, Vladimir Amani, Sujatha Venkataraman, Rakeb T Lemma, Eric W Prince, Andrew Donson, Erin E Moroze, Lindsey Hoffman, Jean M Mulcahy Levy, Nicholas Foreman, Rajeev Vibhakar, Adam L Green
Diffuse intrinsic pontine glioma (DIPG) is an incurable childhood brain tumor. The mechanistic target of rapamycin (MTOR), a key oncogene, functions as two distinct signaling complexes, MTORC1 and MTORC2. We set out to determine the preclinical efficacy and mechanism of action of MTOR inhibitors in DIPG. We evaluated the MTORC1 inhibitor everolimus and the MTORC1/2 inhibitor AZD2014 in three patient-derived DIPG cell lines using cell culture models. We created dose-response curves for both compounds. We measured phenotypic effects on cell self-renewal, apoptosis, cell cycle, differentiation, senescence, and autophagy...
November 29, 2017: Oncology Reports
https://www.readbyqxmd.com/read/29204135/recombinant-uncarboxylated-osteocalcin-per-se-enhances-mouse-skeletal-muscle-glucose-uptake-in-both-extensor-digitorum-longus-and-soleus-muscles
#16
Xuzhu Lin, Lewan Parker, Emma Mclennan, Xinmei Zhang, Alan Hayes, Glenn McConell, Tara C Brennan-Speranza, Itamar Levinger
Emerging evidence suggests that undercarboxylated osteocalcin (ucOC) improves muscle glucose uptake in rodents. However, whether ucOC can directly increase glucose uptake in both glycolytic and oxidative muscles and the possible mechanisms of action still need further exploration. We tested the hypothesis that ucOC per se stimulates muscle glucose uptake via extracellular signal-regulated kinase (ERK), adenosine monophosphate-activated protein kinase (AMPK), and/or the mechanistic target of rapamycin complex 2 (mTORC2)-protein kinase B (AKT)-AKT substrate of 160 kDa (AS160) signaling cascade...
2017: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/29195143/metabolite-identification-and-pharmacokinetic-profiling-of-pp242-an-atp-competitive-inhibitor-of-mtor-using-ultra-high-performance-liquid-chromatography-and-mass-spectrometry
#17
Md Mamunur Rashid, Hyunbeom Lee, Byung Hwa Jung
PP242 is a second generation novel selective ATP-competitive inhibitor of mTOR that displayed promising anti-cancer activity over several cancer types by inhibiting both the complexes of mTOR (mTORC1 and mTORC2). The purpose of this study is to identify the possible metabolites and to evaluate the pharmacokinetic profile of PP242 after a single oral administration to Sprague-Dawley (SD) rats. Two metabolites, including one phase I and one phase II, were identified by in vitro and in vivo studies using rat liver microsomes (RLMs) as well as rat plasma, urine and feces, respectively, through ultra high-performance liquid chromatography-linear ion trap quadrupole-orbitrap-mass spectrometry (UHPLC-LTQ-Orbitrap-MS)...
November 23, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/29179463/olaquindox-disrupts-tight-junction-integrity-and-cytoskeleton-architecture-in-mouse-sertoli-cells
#18
Di Wu, Chun-Jie Huang, Xiao-Fei Jiao, Zhi-Ming Ding, Jia-Yu Zhang, Fan Chen, Yong-Sheng Wang, Xiang Li, Li-Jun Huo
Sertoli cells, by creating an immune-privileged and nutrition supporting environment, maintain mammalian spermatogenesis and thereby holds the heart of male fertility. Olaquindox, an effective feed additive in livestock industry, could potentially expose human into the risk of biological hazards due to its genotoxicity and cytotoxicity, highlighting the significance of determining its bio-safety regarding human reproduction. Herein, we deciphered the detrimental effects of olaquindox on male fertility by mechanistically unraveling how olaquindox intervenes blood-testis barrier in mouse...
October 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/29175420/%C3%AE-1a-adrenoceptors-activate-mtor-signalling-and-glucose-uptake-in-cardiomyocytes
#19
Masaaki Sato, Bronwyn A Evans, Anna L Sandström, Ling Yeong Chia, Saori Mukaida, Bui San Thai, Anh Nguyen, Linzi Lim, Christina Yr Tan, Jo-Anne Baltos, Paul J White, Lauren T May, Dana S Hutchinson, Roger J Summers, Tore Bengtsson
The capacity of G protein-coupled receptors to modulate mammalian target of rapamycin (mTOR) activity is a newly emerging paradigm with the potential to link cell surface receptors with cell survival. Cardiomyocyte viability is linked to signaling pathways involving Akt and mTOR, as well as increased glucose uptake and utilization. Our aim was to determine whether the α1A-adrenoceptor (AR) couples to these protective pathways, and increased glucose uptake. We characterised α1A-AR signalling in CHO-K1 cells co-expressing the human α1A-AR and GLUT4 (CHOα1AGLUT4myc) and in neonatal rat ventricular cardiomyocytes (NRVM), and measured glucose uptake, intracellular Ca2+ mobilization, and phosphorylation of mTOR, Akt, 5' adenosine monophosphate-activated kinase (AMPK) and S6 ribosomal protein...
November 23, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29166588/regulatory-t-cell-migration-is-dependent-on-glucokinase-mediated-glycolysis
#20
Madhav Kishore, Kenneth C P Cheung, Hongmei Fu, Fabrizia Bonacina, Guosu Wang, David Coe, Eleanor J Ward, Alessandra Colamatteo, Maryam Jangani, Andrea Baragetti, Giuseppe Matarese, David M Smith, Robert Haas, Claudio Mauro, David C Wraith, Klaus Okkenhaug, Alberico L Catapano, Veronica De Rosa, Giuseppe D Norata, Federica M Marelli-Berg
Migration of activated regulatory T (Treg) cells to inflamed tissue is crucial for their immune-modulatory function. While metabolic reprogramming during Treg cell differentiation has been extensively studied, the bioenergetics of Treg cell trafficking remains undefined. We have investigated the metabolic demands of migrating Treg cells in vitro and in vivo. We show that glycolysis was instrumental for their migration and was initiated by pro-migratory stimuli via a PI3K-mTORC2-mediated pathway culminating in induction of the enzyme glucokinase (GCK)...
November 21, 2017: Immunity
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