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mTOR inhibition

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https://www.readbyqxmd.com/read/28918598/triacsin-c-reduces-lipid-droplet-formation-and-induces-mitochondrial-biogenesis-in-primary-rat-hepatocytes
#1
Carlos R P Dechandt, Felippe H Zuccolotto-Dos-Reis, Bruno G Teodoro, Anna Maria A P Fernandes, Marcos N Eberlin, Isis C Kettelhut, Carlos Curti, Luciane C Alberici
Intracellular long-chain acyl-CoA synthetases (ACSL) activate fatty acids to produce acyl-CoA, which undergoes β-oxidation and participates in the synthesis of esterified lipids such as triacylglycerol (TAG). Imbalances in these metabolic routes are closely associated with the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Triacsin C is one of the few compounds that inhibit TAG accumulation into lipid droplets (LD) by suppressing ACSL activity. Here we report that treatment of primary rat hepatocytes with triacsin C at concentrations lower than the IC50 (4...
September 16, 2017: Journal of Bioenergetics and Biomembranes
https://www.readbyqxmd.com/read/28918027/adeno-associated-viral-vector-mediated-mtor-inhibition-by-short-hairpin-rna-suppresses-laser-induced-choroidal-neovascularization
#2
Tae Kwann Park, Si Hyung Lee, Jun Sub Choi, Seung Kwan Nah, Hee Jong Kim, Ha Yan Park, Heuiran Lee, Steven Hyun Seung Lee, Keerang Park
Choroidal neovascularization (CNV) is the defining characteristic feature of the wet subtype of age-related macular degeneration (AMD) and may result in irreversible blindness. Based on anti-vascular endothelial growth factor (anti-VEGF), the current therapeutic approaches to CNV are fraught with difficulties, and mammalian target of rapamycin (mTOR) has recently been proposed as a possible therapeutic target, although few studies have been conducted. Here, we show that a recombinant adeno-associated virus-delivered mTOR-inhibiting short hairpin RNA (rAAV-mTOR shRNA), which blocks the activity of both mTOR complex 1 and 2, represents a promising therapeutic approach for the treatment of CNV...
September 15, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28917508/insulin-dependent-metabolic-and-inotropic-responses-in-the-heart-are-modulated-by-hydrogen-peroxide-from-nadph-oxidase-isoforms-nox2-and-nox4
#3
Benjamin Steinhorn, Juliano L Sartoretto, Andrea Sorrentino, Natalia Romero, Hermann Kalwa, E Dale Abel, Thomas Michel
RATIONALE: Hydrogen peroxide (H2O2) is a stable reactive oxygen species (ROS) that has long been implicated in insulin signal transduction in adipocytes. However, H2O2's role in mediating insulin's effects on the heart are unknown. OBJECTIVE: We investigated the role of H2O2 in activating insulin-dependent changes in cardiac myocyte metabolic and inotropic pathways. The sources of insulin-dependent H2O2 generation were also studied. METHODS AND RESULTS: In addition to the canonical role of insulin in modulating cardiac metabolic pathways, we found that insulin also inhibited beta adrenergic-induced increases in cardiac contractility...
September 13, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28916818/identification-of-4-phenylquinolin-2-1h-one-as-a-specific-allosteric-inhibitor-of-akt
#4
Bill X Huang, Kenny Newcomer, Karl Kevala, Elena Barnaeva, Wei Zheng, Xin Hu, Samarjit Patnaik, Noel Southall, Juan Marugan, Marc Ferrer, Hee-Yong Kim
Akt plays a major role in tumorigenesis and the development of specific Akt inhibitors as effective cancer therapeutics has been challenging. Here, we report the identification of a highly specific allosteric inhibitor of Akt through a FRET-based high-throughput screening, and characterization of its inhibitory mechanism. Out of 373,868 compounds screened, 4-phenylquinolin-2(1H)-one specifically decreased Akt phosphorylation at both T308 and S473, and inhibited Akt kinase activity (IC50 = 6 µM) and downstream signaling...
September 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28916338/structure-activity-relationship-study-of-small-molecule-inhibitors-of-the-deptor-mtor-interaction
#5
Jihye Lee, Yijiang Shi, Mario Vega, Yonghui Yang, Joseph Gera, Michael E Jung, Alan Lichtenstein
DEPTOR is a 48kDa protein that binds to mTOR and inhibits this kinase within mTORC1 and mTORC2 complexes. Over-expression of DEPTOR specifically occurs in the multiple myeloma (MM) tumor model and DEPTOR knockdown is cytotoxic to MM cells, suggesting it is a potential therapeutic target. Since mTORC1 paralysis protects MM cells against DEPTOR knockdown, it indicates that the protein-protein interaction between DEPTOR and mTOR is key to MM viability vs death. In a previous study, we used a yeast two-hybrid screen of a small inhibitor library to identify a compound that inhibited DEPTOR/mTOR binding in yeast...
September 6, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28916337/angiotensin-ii-induces-calcium-mediated-autophagy-in-podocytes-through-enhancing-reactive-oxygen-species-levels
#6
Na Gao, Hui Wang, Hongqiang Yin, Zhuo Yang
As well known, abnormalities of Angiotensin II (Ang II) is closely related with glomerular damage. This study was to investigate whether Ang II could affect autophagy in podocytes via oxidative stress, and whether autophagy had a positive role in protecting podocytes impaired by Ang II. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that Ang II induced podocyte death. The measurements of malondialdehyde (MDA) and H2O2 levels, and flow cytometry assay revealed that Ang II considerably increased ROS generation in podocytes...
September 12, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/28915623/inhibition-of-the-pi3k-akt-mtor-pathway-activates-autophagy-and-compensatory-ras-raf-mek-erk-signalling-in-prostate-cancer
#7
Dominika E Butler, Christopher Marlein, Hannah F Walker, Fiona M Frame, Vincent M Mann, Matthew S Simms, Barry R Davies, Anne T Collins, Norman J Maitland
The PI3K/AKT/mTOR pathway is frequently activated in advanced prostate cancer, due to loss of the tumour suppressor PTEN, and is an important axis for drug development. We have assessed the molecular and functional consequences of pathway blockade by inhibiting AKT and mTOR kinases either in combination or as individual drug treatments. In established prostate cancer cell lines, a decrease in cell viability and in phospho-biomarker expression was observed. Although apoptosis was not induced, a G1 growth arrest was observed in PTEN null LNCaP cells, but not in BPH1 or PC3 cells...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28915569/gabarapl1-tumor-suppressive-function-is-independent-of-its-conjugation-to-autophagosomes-in-mcf-7-breast-cancer-cells
#8
Laura Poillet-Perez, Marine Jacquet, Eric Hervouet, Thierry Gauthier, Annick Fraichard, Christophe Borg, Jean-René Pallandre, Bruno J Gonzalez, Yasmina Ramdani, Michaël Boyer-Guittaut, Régis Delage-Mourroux, Gilles Despouy
The GABARAPL1 protein belongs to the ATG8 family whose members are involved in autophagy. Our laboratory previously demonstrated that GABARAPL1 associates with autophagic vesicles, regulates autophagic flux and acts as a tumor suppressor protein in breast cancer. In this study, we aimed to determine whether GABARAPL1 conjugation to autophagosomes is necessary for its tumor suppressive functions using the MCF-7 breast cancer cell line overexpressing GABARAPL1 or a G116A mutant, which is unable to be lipidated and associated to autophagosomes...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28915568/hyperosmotic-stress-stimulates-autophagy-via-polycystin-2
#9
Daniel Peña-Oyarzun, Rodrigo Troncoso, Catalina Kretschmar, Cecilia Hernando, Mauricio Budini, Eugenia Morselli, Sergio Lavandero, Alfredo Criollo
Various intracellular mechanisms are activated in response to stress, leading to adaptation or death. Autophagy, an intracellular process that promotes lysosomal degradation of proteins, is an adaptive response to several types of stress. Osmotic stress occurs under both physiological and pathological conditions, provoking mechanical stress and activating various osmoadaptive mechanisms. Polycystin-2 (PC2), a membrane protein of the polycystin family, is a mechanical sensor capable of activating the cell signaling pathways required for cell adaptation and survival...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28912571/comparative-global-immune-related-gene-profiling-of-somatic-cells-human-pluripotent-stem-cells-and-their-derivatives-implication-for-human-lymphocyte-proliferation
#10
Chia-Eng Wu, Chen-Wei Yu, Kai-Wei Chang, Wen-Hsi Chou, Chen-Yu Lu, Elisa Ghelfi, Fang-Chun Wu, Pey-Shynan Jan, Mei-Chi Huang, Patrick Allard, Shau-Ping Lin, Hong-Nerng Ho, Hsin-Fu Chen
Human pluripotent stem cells (hPSCs), including embryonic stem cells (ESCs) and induced PSCs (iPSCs), represent potentially unlimited cell sources for clinical applications. Previous studies have suggested that hPSCs may benefit from immune privilege and limited immunogenicity, as reflected by the reduced expression of major histocompatibility complex class-related molecules. Here we investigated the global immune-related gene expression profiles of human ESCs, hiPSCs and somatic cells and identified candidate immune-related genes that may alter their immunogenicity...
September 15, 2017: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/28912474/rhus-coriaria-increases-protein-ubiquitination-proteasomal-degradation-and-triggers-non-canonical-beclin-1-independent-autophagy-and-apoptotic-cell-death-in-colon-cancer-cells
#11
Khawlah Athamneh, Hussain El Hasasna, Halima Al Samri, Samir Attoub, Kholoud Arafat, Nehla Benhalilou, Asma Al Rashedi, Yusra Al Dhaheri, Synan AbuQamar, Ali Eid, Rabah Iratni
Colorectal cancer is the fourth leading cause of cancer-related deaths worldwide. Here, we investigated the anticancer effect of Rhus coriaria extract (RCE) on HT-29 and Caco-2 human colorectal cancer cells. We found that RCE significantly inhibited the viability and colony growth of colon cancer cells. Moreover, RCE induced Beclin-1-independent autophagy and subsequent caspase-7-dependent apoptosis. Blocking of autophagy by chloroquine significantly reduced RCE-induced cell death, while blocking of apoptosis had no effect on RCE-induced cell death...
September 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28912095/globularifolin-exerts-anticancer-effects-on-glioma-u87%C3%A2-cells-through-inhibition-of-akt-mtor-and-mek-erk-signaling-pathways-in-vitro-and-inhibits-tumor-growth-in-vivo
#12
Yunhu Yu, Xiaohong Fu, Qishan Ran, Kaihua Yang, Yuanchao Wen, Hang Li, Fei Wang
Gliomas are the most recurrently occurring primary malignancies in the central nervous system. Despite surgical interventions, chemo- and radiotherapy, the results are unfortunately poor. Therefore, there is pressing need to explore more effective and efficient treatment options for treatment of glioma. In the present study we determined the anticancer potential of globularifolin against human glioma U87 cell line and human astrocytes. The results showed that globularifolin exhibits an IC50 value of 7.5 μM against glioma U87 cells as against the IC50 of 65 μM against human astrocytes...
September 11, 2017: Biochimie
https://www.readbyqxmd.com/read/28912059/piracetam-inhibits-ethanol-etoh-induced-memory-deficit-by-mediating-multiple-pathways
#13
Yifan Yang, Jian Feng, Fangyuan Xu, Jianglin Wang
Excessive ethanol (EtOH) intake, especially to prenatal exposure, can significantly affect cognitive function and cause permanent learning and memory injures in children. As a result, how to protect children from EtOH neurotoxicity has gained increasing attention in recent years. Piracetam (Pir) is a nootropic drug derived from c-aminobutyric acid and can manage cognition impairments in multiple neurological disorders. Studies have shown that Pir can exert therapeutic effects on EtOH-induced memory impairments, but the underlying mechanism is still unknown...
September 11, 2017: Brain Research
https://www.readbyqxmd.com/read/28906486/small-molecule-rl71-triggered-excessive-autophagic-cell-death-as-a-potential-therapeutic-strategy-in-triple-negative-breast-cancer
#14
Jian Gao, Minmin Fan, Shuang Peng, Minxia Zhang, Gang Xiang, Xin Li, Wenjie Guo, Yang Sun, Xuefeng Wu, Xudong Wu, Guang Liang, Yan Shen, Qiang Xu
Triple-negative breast cancer (TNBC) has an aggressive phenotype and a poor prognosis owing to the high propensity for metastatic progression and the absence of specific targeted treatment. Here, we revealed that small-molecule RL71 targeting sarco/endoplasmic reticulum calcium-ATPase 2 (SERCA2) exhibited potent anti-cancer activity on all TNBC cells tested. Apart from apoptosis induction, RL71 triggered excessive autophagic cell death, the main contributor to RL71-induced TNBC cell death. RL71 augmented the release of Ca(2+) from the endoplasmic reticulum (ER) into the cytosol by inhibiting SERCA2 activity...
September 14, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28905991/target-of-rapamycin-signaling-orchestrates-growth-defense-trade-offs-in-plants
#15
David De Vleesschauwer, Osvaldo Filipe, Gena Hoffman, Hamed Soren Seifi, Ashley Haeck, Patrick Canlas, Jonas Van Bockhaven, Evelien De Waele, Kristof Demeestere, Pamela Ronald, Monica Hofte
Plant defense to microbial pathogens is often accompanied by significant growth inhibition. How plants merge immune system function with normal growth and development is still poorly understood. Here, we investigated the role of target of rapamycin (TOR), an evolutionary conserved serine/threonine kinase, in the plant defense response. We used rice as a model system and applied a combination of chemical, genetic, genomic and cell-based analyses. We demonstrate that ectopic expression of TOR and Raptor (regulatory-associated protein of mTOR), a protein previously demonstrated to interact with TOR in Arabidopsis, positively regulates growth and development in rice...
September 14, 2017: New Phytologist
https://www.readbyqxmd.com/read/28905990/the-mtor-kinase-inhibitor-everolimus-synergistically-enhances-the-anti-tumor-effect-of-the-bruton-s-tyrosine-kinase-btk-inhibitor-pls-123-on-mantle-cell-lymphoma
#16
Jiao Li, Xiaogan Wang, Yan Xie, Zhitao Ying, Weiping Liu, Lingyan Ping, Chen Zhang, Zhengying Pan, Ning Ding, Yuqin Song, Jun Zhu
Mantle cell lymphoma (MCL) is an aggressive and incurable malignant disease. Despite of general chemotherapy, relapse and mortality are common, highlighting the need for the development of novel targeted drugs or combination of therapeutic regimens. Recently, several drugs that target the B-cell receptor (BCR) signaling pathway, especially the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, have demonstrated notable therapeutic effects in relapsed/refractory patients, which indicate that pharmacological inhibition of BCR pathway holds promise in MCL treatment...
September 14, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28905500/salidroside-suppressing-lps-induced-myocardial-injury-by-inhibiting-ros-mediated-pi3k-akt-mtor-pathway-in-vitro-and-in-vivo
#17
Lvyi Chen, Peng Liu, Xin Feng, Chunhua Ma
The purpose of the present study was to investigate the effect of salidroside (Sal) on myocardial injury in lipopolysaccharide (LPS)-induced endotoxemic in vitro and in vivo. SD rats were randomly divided into five groups: control group, LPS group (15 mg/kg), LPS plus dexamethasone (2 mg/kg), LPS plus Sal groups with different Sal doses (20, 40 mg/kg). Hemodynamic measurement and haematoxylin and eosin staining were performed. Serum levels of creatine kinase (CK), lactate dehydrogenase, the activities of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-px), glutathione, tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) were measured after the rats were killed...
September 14, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28903445/predicting-clinical-benefit-from-everolimus-in-patients-with-advanced-solid-tumors-the-cpct-03-study
#18
Fleur Weeber, Geert A Cirkel, Marlous Hoogstraat, Sander Bins, Christa G M Gadellaa-van Hooijdonk, Salo Ooft, Erik van Werkhoven, Stefan M Willems, Marijn van Stralen, Wouter B Veldhuis, Nicolle J M Besselink, Hugo M Horlings, Neeltje Steeghs, Maja J de Jonge, Marlies H G Langenberg, Lodewyk F A Wessels, Edwin P J G Cuppen, J H Schellens, Stefan Sleijfer, Martijn P Lolkema, Emile E Voest
BACKGROUND: In this study, our aim was to identify molecular aberrations predictive for response to everolimus, an mTOR inhibitor, regardless of tumor type. METHODS: To generate hypotheses about potential markers for sensitivity to mTOR inhibition, drug sensitivity and genomic profiles of 835 cell lines were analyzed. Subsequently, a multicenter study was conducted. Patients with advanced solid tumors lacking standard of care treatment options were included and underwent a pre-treatment tumor biopsy to enable DNA sequencing of 1,977 genes, derive copy number profiles and determine activation status of pS6 and pERK...
August 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28903425/pasireotide-is-more-effective-than-octreotide-alone-or-combined-with-everolimus-on-human-meningioma-in-vitro
#19
Thomas Graillon, David Romano, Céline Defilles, Christophe Lisbonis, Alexandru Saveanu, Dominique Figarella-Branger, Pierre-Hugues Roche, Stéphane Fuentes, Olivier Chinot, Henry Dufour, Anne Barlier
Pasireotide is a somatostatin analog (SSA) that targets somatostatin receptor subtype 1 (SST1), SST2, SST3, and SST5 with a high affinity. Pasireotide has a better antisecretory effect in acromegaly, Cushing's disease, and neuroendocrine tumors than octreotide. In this study, we compared the effects of pasireotide to those of octreotide in vitro on meningioma primary cell cultures, both alone and in combination with the mTOR inhibitor everolimus. Significant mRNA expression levels of SST1, SST2, and SST5 were observed in 40...
August 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28903416/overriding-tki-resistance-of-renal-cell-carcinoma-by-combination-therapy-with-il-6-receptor-blockade
#20
Kei Ishibashi, Tobias Haber, Ines Breuksch, Susanne Gebhard, Takashi Sugino, Hitoshi Kubo, Junya Hata, Tomoyuki Koguchi, Michihiro Yabe, Masao Kataoka, Soichiro Ogawa, Hiroyuki Hiraki, Tomohiko Yanagida, Nobuhiro Haga, Joachim W Thüroff, Dirk Prawitt, Walburgis Brenner, Yoshiyuki Kojima
Metastatic renal cell carcinoma (RCC) is a tumor entity with poor prognosis due to limited therapy options. Tyrosine kinase inhibitors (TKI) represent the standard of care for RCCs, however a significant proportion of RCC patients develop resistance to this therapy. Interleukin-6 (IL-6) is considered to be associated with poor prognosis in RCCs. We therefore hypothesized that TKI resistance and IL-6 secretion are causally connected. We first analyzed IL-6 expression after TKI treatment in RCC cells and RCC tumor specimens...
August 15, 2017: Oncotarget
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