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https://www.readbyqxmd.com/read/28829944/spatial-activation-of-torc1-is-regulated-by-hedgehog-and-e2f1-signaling-in-the-drosophila-eye
#1
Wonho Kim, Yoon-Gu Jang, Jinsung Yang, Jongkyeong Chung
Target of rapamycin complex 1 (TORC1) regulates cell growth in response to nutrients and growth factors. Although TORC1 signaling has been thoroughly studied at the cellular level, the regulation of TORC1 in multicellular tissues and organs has remained elusive. Here we found that TORC1 is selectively activated in the second mitotic wave (SMW), the terminal synchronous cell division, of the developing Drosophila eye. We demonstrated that Hedgehog (Hh) signaling regulates TORC1 through E2F1 and the cyclin D/Cdk4 complex in the SMW, and this regulation is independent from insulin and amino acid signaling pathways...
August 21, 2017: Developmental Cell
https://www.readbyqxmd.com/read/28829592/5-4-6-dimorpholino-1-3-5-triazin-2-yl-4-trifluoromethyl-pyridin-2-amine-pqr309-a-potent-brain-penetrant-orally-bioavailable-pan-class-i-pi3k-mtor-inhibitor-as-clinical-candidate-in-oncology
#2
Florent Beaufils, Natasa Cmiljanovic, Vladimir Cmiljanovic, Thomas Bohnacker, Anna Melone, Romina Marone, Eileen Jackson, Xuxiao Zhang, Alexander Sele, Chiara Borsari, Jürgen Mestan, Paul Hebeisen, Petra Hillmann, Bernd Giese, Marketa Zvelebil, Doriano Fabbro, Roger L Williams, Denise Rageot, Matthias P Wymann
Phosphoinositide-3-kinase (PI3K) is deregulated in a wide variety of human tumors, and triggers activation of protein kinase B (PKB/Akt) and mammalian target of rapamycin (mTOR). Here we describe the preclinical characterization of PQR309, a potent 4,6-dimorpholino-1,3,5-triazine-based pan-class I PI3K inhibitor, which targets mTOR kinase in a balanced fashion at higher concentrations. No off-target interactions were detected for PQR309 in a wide panel of protein kinase, enzyme, and receptor ligand assays. Moreover, PQR309 did not bind tubulin, which was observed for the structurally related BKM120 (buparlisib)...
August 22, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28829499/multimodal-oncological-approach-in-patients-affected-by-recurrent-hepatocellular-carcinoma-after-liver-transplantation
#3
G P Guerrini, M Berretta, G Tarantino, P Magistri, A Pecchi, R Ballarin, F Di Benedetto
OBJECTIVE: Hepatocellular Carcinoma (HCC) represents the fifth most common malignancy and the third cancer-related cause of death worldwide. Liver transplantation (LT) is an excellent treatment for patients with small HCC associated with cirrhosis. The purpose of this review is to investigate the possible strategies for the treatment of HCC recurrence after LT based on current clinical evidence. MATERIALS AND METHODS: A systematic literature search was performed independently by two of the authors using PubMed, EMBASE, Scopus and the Cochrane Library Central...
August 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/28827473/restoration-of-circulating-mfge8-milk-fat-globule-egf-factor-8-attenuates-cardiac-hypertrophy-through-inhibition-of-akt-pathway
#4
Ke-Qiong Deng, Jing Li, Zhi-Gang She, Jun Gong, Wen-Lin Cheng, Fu-Han Gong, Xue-Yong Zhu, Yan Zhang, Zhihua Wang, Hongliang Li
Cardiac hypertrophy occurs in response to numerous stimuli like neurohumoral stress, pressure overload, infection, and injury, and leads to heart failure. Mfge8 (milk fat globule-EGF factor 8) is a secreted protein involved in various human diseases, but its regulation and function during cardiac hypertrophy remain unexplored. Here, we found that circulating MFGE8 levels declined significantly in failing hearts from patients with dilated cardiomyopathy. Correlation analyses revealed that circulating MFGE8 levels were negatively correlated with the severity of cardiac dysfunction and remodeling in affected patients...
August 21, 2017: Hypertension
https://www.readbyqxmd.com/read/28827472/inhibition-of-mammalian-target-of-rapamycin-complex-1-attenuates-salt-induced-hypertension-and-kidney-injury-in-dahl-salt-sensitive-rats
#5
Vikash Kumar, Clayton Wollner, Theresa Kurth, John D Bukowy, Allen W Cowley
The goal of the present study was to explore the protective effects of mTORC1 (mammalian target of rapamycin complex 1) inhibition by rapamycin on salt-induced hypertension and kidney injury in Dahl salt-sensitive (SS) rats. We have previously demonstrated that H2O2 is elevated in the kidneys of SS rats. The present study showed a significant upregulation of renal mTORC1 activity in the SS rats fed a 4.0% NaCl for 3 days. In addition, renal interstitial infusion of H2O2 into salt-resistant Sprague Dawley rats for 3 days was also found to stimulate mTORC1 activity independent of a rise of arterial blood pressure...
August 21, 2017: Hypertension
https://www.readbyqxmd.com/read/28826933/safety-and-efficacy-of-docetaxel-bevacizumab-and-everolimus-for-castration-resistant-prostate-cancer-crpc
#6
Mitchell E Gross, Tanya B Dorff, David I Quinn, Patricia M Diaz, Olga O Castellanos, David B Agus
BACKGROUND: Previous data suggests that co-targeting mammalian target of rapamycin and angiogenic pathways may potentiate effects of cytotoxic chemotherapy. We studied combining mammalian target of rapamycin and vascular endothelial growth factor inhibition with docetaxel in castrate-resistant prostate cancer (CRPC). METHODS: Eligible patients had progressive, metastatic, chemotherapy-naive CRPC. Docetaxel and bevacizumab were given intravenously day 1 with everolimus orally daily on a 21-day cycle across 3 dose levels (75:15:2...
July 14, 2017: Clinical Genitourinary Cancer
https://www.readbyqxmd.com/read/28826719/advanced-glycation-end-products-receptor-rage-controls-myocardial-dysfunction-and-oxidative-stress-in-high-fat-fed-mice-by-sustaining-mitochondrial-dynamics-and-autophagy-lysosome-pathway
#7
Yichi Yu, Lei Wang, Florian Delguste, Arthur Durand, Axel Guilbaud, Clementine Rousselin, Ann Marie Schmidt, Frédéric Tessier, Eric Boulanger, Remi Neviere
Oxidative stress and mitochondrial dysfunction are recognized as major contributors of cardiovascular damage in diabetes and high fat diet (HFD) fed mice. Blockade of receptor for advanced glycation end products (RAGE) attenuates vascular oxidative stress and development of atherosclerosis. We tested whether HFD-induced myocardial dysfunction would be reversed in RAGE deficiency mice, in association with changes in oxidative stress damage, mitochondrial respiration, mitochondrial fission and autophagy-lysosomal pathway...
August 18, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28826365/src-3-plays-a-critical-role-in-human-umbilical-vein-endothelial-cells-by-regulating-the-pi3k-akt-mtor-pathway-in-preeclampsia
#8
Yu Yuan, Nan Shan, Bin Tan, Qinyin Deng, Yangming Liu, Hanbin Wang, Xiaofang Luo, Chengjin He, Xin Luo, Hua Zhang, Philip N Baker, David M Olson, Hongbo Qi
Preeclampsia (PE) is currently thought to be characterized by oxidative stress which may lead to endothelial dysfunction. The normal function of vascular endothelium is essential to vascular homeostasis. Previous studies have shown that steroid receptor coactivator 3 (SRC-3) interacts with estrogen receptors (ERs) which are involved in the vasoprotective effects of estrogen and is also associated with cell migration, invasion, and inflammation; however, its role in PE remains unclear. The main purpose of this study is to identify the role of SRC-3 in the function of human umbilical vein endothelial cells (HUVECs) during the development of PE...
January 1, 2017: Reproductive Sciences
https://www.readbyqxmd.com/read/28823029/experience-of-lung-transplantation-in-patients-with-lymphangioleiomyomatosis-at-a-brazilian-reference-centre
#9
Bruno Guedes Baldi, Marcos Naoyuki Samano, Silvia Vidal Campos, Martina Rodrigues de Oliveira, José Eduardo Afonso Junior, Rafael Medeiros Carraro, Ricardo Henrique Oliveira Braga Teixeira, Isabela Pasqualini Minguini, Roni Burlina, Eduardo Zinoni Silva Pato, Carlos Roberto Ribeiro Carvalho, André Nathan Costa
INTRODUCTION: Lung transplantation (LT) is the standard of care for patients with advanced lung diseases, including lymphangioleiomyomatosis (LAM). LAM accounts for only 1% of all LTs performed in the international registry. As a result, the global experience, including the use of mechanistic target of rapamycin (mTOR) inhibitors before and after LT in LAM, is still limited. METHODS: We conducted a retrospective review of all LAM patients who underwent LT at our centre between 2003 and 2016...
August 19, 2017: Lung
https://www.readbyqxmd.com/read/28822990/%C3%AE-%C3%AE-mangostins-induces-autophagy-and-shows-synergistic-effectwith-gemcitabine-in-pancreatic-cancer-cell-lines
#10
Myoungjae Kim, Young-Won Chin, Eun Joo Lee
Pancreatic cancer is one of the most lethal and aggressive cancers in the world. However, no effective treatment is currently available for pancreatic cancer. The objective of this study was to determine the anti-pancreatic cancer effect of α-mangostin (αM) and γ-mangostin (γM) extracted from the pericarp of Garcinia mangostana L.. Both αM and γM reduced the viability of pancreatic cancer cells MIA PaCa-2 and PANC-1 in a dose-dependent manner. These compounds induced apoptosis by increasing c-PARP and c-Caspase 3 levels...
August 21, 2017: Biomolecules & Therapeutics
https://www.readbyqxmd.com/read/28822888/apatinib-enhances-antitumour-activity-of-egfr-tkis-in-non-small-cell-lung-cancer-with-egfr-tki-resistance
#11
Fang Li, Tengjiao Zhu, Baoshan Cao, Jiadong Wang, Li Liang
BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs)-rechallenged therapy for EGFR-mutant non-small cell lung cancer (NSCLC) patients who acquired resistance showed moderate efficacy. Considering the high interrelation between EGFR and vascular endothelial growth factor/vascular endothelial growth factor receptor (VEGF/VEGFR) pathways, we firstly evaluated EGFR-TKI combined with apatinib (a highly selective VEGFR2 inhibitor) in EGFR-TKI-resistant model and patients...
August 17, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28822838/scavenging-reactive-oxygen-species-inhibits-status-epilepticus-induced-neuroinflammation
#12
Pallavi B McElroy, Li-Ping Liang, Brian J Day, Manisha Patel
Inflammation has been identified as an important mediator of seizures and epileptogenesis. Understanding the mechanisms underlying seizure-induced neuroinflammation could lead to the development of novel therapies for the epilepsies. Reactive oxygen species (ROS) are recognized as mediators of seizure-induced neuronal damage and are known to increase in models of epilepsies. ROS are also known to contribute to inflammation in several disease states. We hypothesized that ROS are key modulators of neuroinflammation i...
August 16, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28822689/cholesterol-lowering-gene-therapy-counteracts-the-development-of-non-ischemic-cardiomyopathy-in-mice
#13
Ilayaraja Muthuramu, Ruhul Amin, Andrey Postnov, Mudit Mishra, Joseph Pierre Aboumsallem, Tom Dresselaers, Uwe Himmelreich, Paul P Van Veldhoven, Olivier Gheysens, Frank Jacobs, Bart De Geest
A causal role of hypercholesterolemia in non-ischemic heart failure has never been demonstrated. Adeno-associated viral serotype 8 (AAV8)-low-density lipoprotein receptor (AAV8-LDLr) gene transfer was performed in LDLr-deficient mice without and with pressure overload induced by transverse aortic constriction (TAC). AAV8-LDLr gene therapy resulted in an 82.8% (p < 0.0001) reduction of plasma cholesterol compared with controls. Mortality rate was lower (p < 0.05) in AAV8-LDLr TAC mice compared with control TAC mice (hazard ratio for mortality 0...
August 1, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28822614/heterogeneity-in-a-large-pedigree-with-danon-disease-implications-for-pathogenesis-and-management
#14
Jonathan C P Roos, Matthew J Daniels, Elizabeth Morris, Hanna I Hyry, Timothy M Cox
BACKGROUND: Danon disease is an X-linked disturbance of autophagy manifesting with cognitive impairment and disordered heart and skeletal muscle. After a period of relative stability, patients deteriorate rapidly and may quickly become ineligible for elective heart transplantation - the only life-saving therapy. METHODS: We report a large pedigree with diverse manifestations of Danon disease in hemizygotes and female heterozygotes. RESULTS: Malignant cardiac arrhythmias requiring amiodarone treatment induced thyroid disease in two patients; intractable thyrotoxicosis, which enhances autophagy, caused the death of a 21year-old man...
June 21, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28822229/vasculogenesis-and-angiogenesis-initiation-under-normoxic-conditions-through-wnt-%C3%AE-catenin-pathway-in-gliomas
#15
Alexandre Vallée, Rémy Guillevin, Jean-Noël Vallée
The canonical Wnt/β-catenin pathway is up-regulated in gliomas and involved in proliferation, invasion, apoptosis, vasculogenesis and angiogenesis. Nuclear β-catenin accumulation correlates with malignancy. Hypoxia activates hypoxia-inducible factor (HIF)-1α by inhibiting HIF-1α prolyl hydroxylation, which promotes glycolytic energy metabolism, vasculogenesis and angiogenesis, whereas HIF-1α is degraded by the HIF prolyl hydroxylase under normoxic conditions. We focus this review on the links between the activated Wnt/β-catenin pathway and the mechanisms underlying vasculogenesis and angiogenesis through HIF-1α under normoxic conditions in gliomas...
August 19, 2017: Reviews in the Neurosciences
https://www.readbyqxmd.com/read/28822061/co-ultramicronized-palmitoylethanolamide-luteolin-facilitates-the-development-of-differentiating-and-undifferentiated-rat-oligodendrocyte-progenitor-cells
#16
Stephen D Skaper, Massimo Barbierato, Laura Facci, Mila Borri, Gabriella Contarini, Morena Zusso, Pietro Giusti
Oligodendrocytes, the myelin-producing cells of the central nervous system (CNS), have limited capability to bring about repair in chronic CNS neuroinflammatory demyelinating disorders such as multiple sclerosis (MS). MS lesions are characterized by a compromised pool of undifferentiated oligodendrocyte progenitor cells (OPCs) unable to mature into myelin-producing oligodendrocytes. An attractive strategy may be to replace lost OLs and/or promote their maturation. N-palmitoylethanolamine (PEA) is an endogenous fatty acid amide signaling molecule with anti-inflammatory and neuroprotective actions...
August 18, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28821606/flipping-a-citrate-switch-on-liver-cancer-cells
#17
Jeffrey M Peters
Energy homeostasis and oncogenic signaling are critical determinants of the growth of human liver cancer cells, providing a strong rationale to elucidate the regulatory mechanisms for these systems. A new study reports that loss of solute carrier family 13 member 5, which transports citrate across cell membranes, halts liver cancer cell growth by altering both energy production and mammalian target of rapamycin signaling in human liver cancer cell lines and in both an in vitro and in vivo model of liver tumors, suggesting a new target for liver cancer chemoprevention and/or chemotherapy...
August 18, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28821580/cap-independent-translation-ensures-mtor-expression-and-function-upon-protein-synthesis-inhibition
#18
Ana Marques-Ramos, Marco M Candeias, Juliane Menezes, Rafaela Lacerda, Margaret Willcocks, Alexandre Teixeira, Nicolas Locker, Luisa Romao
The mechanistic/mammalian target of rapamycin (mTOR) is a conserved serine/threonine kinase that integrates cellular signals from the nutrient and energy status to act, namely, on the protein synthesis machinery. While major advances have emerged regarding the regulators and effects of mTOR signaling pathway, little is known about the regulation of mTOR gene expression. Here, we show that human mTOR transcript can be translated in a cap-independent manner, and that its 5' untranslated region (UTR) is a highly folded RNA scaffold capable of binding directly to the 40S ribosomal subunit...
August 18, 2017: RNA
https://www.readbyqxmd.com/read/28821013/rictor-positively-regulates-b-cell-receptor-signaling-by-modulating-actin-reorganization-via-ezrin
#19
Lu Huang, Yongjie Zhang, Chenguang Xu, Xiaomei Gu, Linlin Niu, Jinzhi Wang, Xiaoyu Sun, Xiaoming Bai, Xingtian Xuan, Qubei Li, Chunwei Shi, Bing Yu, Heather Miller, Gangyi Yang, Lisa S Westerberg, Wanli Liu, Wenxia Song, Xiaodong Zhao, Chaohong Liu
As the central hub of the metabolism machinery, the mammalian target of rapamycin complex 2 (mTORC2) has been well studied in lymphocytes. As an obligatory component of mTORC2, the role of Rictor in T cells is well established. However, the role of Rictor in B cells still remains elusive. Rictor is involved in B cell development, especially the peripheral development. However, the role of Rictor on B cell receptor (BCR) signaling as well as the underlying cellular and molecular mechanism is still unknown. This study used B cell-specfic Rictor knockout (KO) mice to investigate how Rictor regulates BCR signaling...
August 2017: PLoS Biology
https://www.readbyqxmd.com/read/28820396/the-role-of-mtor-inhibitors-and-hmg-coa-reductase-inhibitors-on-young-and-old-endothelial-cell-functions-critical-for-re-endothelialisation-after-percutaneous-coronary-intervention-an-in-vitro-study
#20
K Korybalska, E Kawka, A Breborowicz, J Witowski
Percutaneous coronary intervention (PCI) has become a standard treatment in patients with acute coronary syndrome. However, it is associated with endothelial cell denudation, which may predispose to in-stent thrombosis and restenosis. Pharmacological methods which prevent restenosis can delay post-PCI re-endothelialisation. We have therefore examined how atorvastatin (HMG-CoA reductase inhibitor), sirolimus and everolimus (mTOR inhibitors) affect young and old endothelial cell functions which are responsible for wound healing after PCI...
June 2017: Journal of Physiology and Pharmacology: An Official Journal of the Polish Physiological Society
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