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https://www.readbyqxmd.com/read/28238805/pharmacological-inhibition-of-lsd1-and-mtor-reduces-mitochondrial-retention-and-associated-ros-levels-in-the-red-blood-cells-of-sickle-cell-disease
#1
Ramasamy Jagadeeswaran, Benjamin A Vazquez, Muthusamy Thiruppathi, Balaji B Ganesh, Vinzon Ibanez, Shuaiying Cui, James D Engel, Alan M Diamond, Robert E Molokie, Joseph DeSimone, Donald Lavelle, Angela Rivers
Sickle cell disease (SCD), an inherited blood disorder caused by a point mutation that renders hemoglobin susceptible to polymerization when deoxygenated, affects millions of people worldwide. Manifestations of SCD include chronic hemolytic anemia, inflammation, painful vaso-occlusive crises, multisystem organ damage, and reduced life expectancy. Part of SCD pathophysiology is the excessive formation of intracellular reactive oxygen species (ROS) in SCD red blood cells (RBCs) which accelerates their hemolysis...
February 23, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28237721/cytoprotective-effect-of-kaempferol-against-palmitic-acid-induced-pancreatic-%C3%AE-cell-death-through-modulation-of-autophagy-via-ampk-mtor-signaling-pathway
#2
Ritu Varshney, Sumeet Gupta, Partha Roy
Lipotoxicity of pancreatic β-cells is the pathological manifestation of obesity-linked type II diabetes. We intended to determine the cytoprotective effect of kaempferol on pancreatic β-cells undergoing apoptosis in palmitic acid (PA)-stressed condition. The data showed that kaempferol treatment increased cell viability and anti-apoptotic activity in PA-stressed RIN-5F cells and murine pancreatic islets. Furthermore, kaempferol's ability to instigate autophagy was illustrated by MDC-LysoTracker red staining and TEM analysis which corroborated well with the observed increase in LC3 puncta and LC3-II protein expressions along with the concomitant decline in p62 expression...
February 22, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28235701/design-synthesis-and-biological-evaluation-of-imidazo-1-2-b-pyridazine-derivatives-as-mtor-inhibitors
#3
Beibei Mao, Shanyun Gao, Yiran Weng, Liangren Zhang, Lihe Zhang
ATP-competitive mTOR inhibitors have been studied as potential antitumor agents. Based on the structure-activity relationship of known mTOR inhibitors, a series of novel imidazo[1,2-b]pyridazine derivatives were synthesized and characterized. The anti-proliferative activities of these compounds were evaluated by SRB assay against six human cancer cell lines. Imidazo[1,2-b]pyridazine diaryl urea derivatives A15-A24 exhibited significant anti-proliferative activity especially against non-small cell lung cancer A549 and H460 with IC50 values ranging from 0...
February 9, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28235656/high-expressing-cystic-fibrosis-transmembrane-conductance-regulator-interacts-with-histone-deacetylase-2-to-promote-the-development-of-ph-leukemia-through-the-hdac2-mediated-pten-pathway
#4
Tianyou Yan, Yamei Leng, Xi Yang, Yuping Gong, Huaqin Sun, Ke Wang, Wenming Xu, Yuhuan Zheng, Duolan Naren, Rui Shi
The aberrant expression or mutation of CFTR has been shown to be involved in several tumors, but how mutations or dysfunction of CFTR may increase the risk of malignancies in various tissues remains unclear. Here, we report the interaction between CFTR and HDAC2, and its involvement in the development of Ph+ leukemia. We first detected the physical interaction and co-localization of CFTR and HDAC2 in Ph+ leukemia cell lines. And treatment with CFTRinh-172, a CFTR inhibitor, reduced the expression of HDAC2 protein in K562 and SUP-B15 cells, which could be partially recovered by MG132, a proteasome inhibitor...
February 16, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28235485/modulation-of-autophagy-in-exjsrv-env-transfected-cells-through-the-akt-mtor-and-mapk-signaling-pathway
#5
Xiaolin Sun, Fangyuan Du, Shuying Liu
The envelope (Env) of Jaagsiekte sheep retrovirus (JSRV) is an oncoprotein of ovine pulmonary adenocarcinoma (OPA). Autophagy is involved in different cancers, but how it is carcinogenic in JSRV Env is unclear. Modulation of autophagy in exJSRV-env-NM-transfected cells through the Akt/mTOR and MAPK signaling pathway was studied, and we observed strong positive labeling of p-Akt, p-mTOR, p-MEK1/2, p-ERK1/2, p-p38 and p-JNK in tumor cells and typical type II pneumocytes in naturally infected OPA lung tissues, which was co-aligned with JSRV-Env positive cells as shown by immunohistochemical and microscopic analysis...
February 21, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28232835/mesenchymal-stem-cells-support-survival-and-proliferation-of-primary-human-acute-myeloid-leukemia-cells-through-heterogeneous-molecular-mechanisms
#6
Annette K Brenner, Ina Nepstad, Øystein Bruserud
Acute myeloid leukemia (AML) is a bone marrow malignancy, and various bone marrow stromal cells seem to support leukemogenesis, including osteoblasts and endothelial cells. We have investigated how normal bone marrow mesenchymal stem cells (MSCs) support the in vitro proliferation of primary human AML cells. Both MSCs and primary AML cells show constitutive release of several soluble mediators, and the mediator repertoires of the two cell types are partly overlapping. The two cell populations were cocultured on transwell plates, and MSC effects on AML cells mediated through the local cytokine/soluble mediator network could thus be evaluated...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28232476/potential-targets-analysis-reveals-dual-pi3k-mtor-pathway-inhibition-as-a-promising-therapeutic-strategy-for-uterine-leiomyosarcomas-an-enitec-group-initiative
#7
Tine Cuppens, Daniela Annibali, An Coosemans, Jone Trovik, Natalja Ter Haar, Eva Colas, Angel Garcia-Jimenez, Koen Van de Vijver, Roy P M Kruitwagen, Mariël Brinkhuis, Michal Zikan, Pavel Dundr, Jutta Huvila, Olli Carpén, Johannes Haybaeck, Farid Moinfar, Helga B Salvesen, Maciej Stukan, Carole Mestdagh, Ronald P Zweemer, Leonardus F Massuger, Michael R Mallmann, Eva Wardelmann, Miriam Mints, Godelieve Verbist, Debby Thomas, Ellen Gommé, Els Hermans, Philippe Moerman, Tjalling Bosse, Frédéric Amant
Purpose: Uterine sarcomas are rare and heterogeneous tumors characterized by an aggressive clinical behavior. Their high rates of recurrence and mortality point to the urgent need for novel targeted therapies and alternative treatment strategies. However, no molecular prognostic or predictive biomarkers are available so far to guide choice and modality of treatment.Experimental Design: We investigated the expression of several druggable targets (phospho-S6(S240) ribosomal protein, PTEN, PDGFR-α, ERBB2, and EGFR) in a large cohort of human uterine sarcoma samples (288), including leiomyosarcomas, low-grade and high-grade endometrial stromal sarcomas, undifferentiated uterine sarcomas, and adenosarcomas, together with 15 smooth muscle tumors of uncertain malignant potential (STUMP), 52 benign uterine stromal tumors, and 41 normal uterine tissues...
February 23, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28231559/prostate-cancer-heterogeneity-discovering-novel-molecular-targets-for-therapy
#8
REVIEW
Chiara Ciccarese, Francesco Massari, Roberto Iacovelli, Michelangelo Fiorentino, Rodolfo Montironi, Vincenzo Di Nunno, Francesca Giunchi, Matteo Brunelli, Giampaolo Tortora
Prostate cancer (PCa) shows a broad spectrum of biological and clinical behavior, which represents the epiphenomenon of an extreme genetic heterogeneity. Recent genomic profiling studies have deeply improved the knowledge of the genomic landscape of localized and metastatic PCa. The AR and PI3K/Akt/mTOR signaling pathways are the two most frequently altered, representing therefore interestingly targets for therapy. Moreover, somatic or germline aberrations of DNA repair genes (DRGs) have been observed at high frequency, supporting the potential role of platinum derivatives and PARP inhibitors as effective therapeutic strategies...
February 11, 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/28230853/mesenchymal-stromal-cells-inhibit-cd25-expression-via-the-mtor-pathway-to-potentiate-t-cell-suppression
#9
Hyun Seung Yoo, Kyuheon Lee, Kwangmin Na, Yong Xu Zhang, Hyun-Ja Lim, TacGhee Yi, Sun U Song, Myung-Shin Jeon
Mesenchymal stromal cells (MSCs) are known to suppress T-cell activation and proliferation. Several studies have reported that MSCs suppress CD25 expression in T cells. However, the molecular mechanism underlying MSC-mediated suppression of CD25 expression has not been fully examined. Here, we investigated the mTOR pathway, which is involved in CD25 expression in T cells. We showed that MSCs inhibited CD25 expression, which was restored in the presence of an inducible nitric oxide synthase (iNOS) inhibitor...
February 23, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28230643/mtor-inhibition-clinical-transplantation-pancreas-islet
#10
Thierry Berney, Axel Andres, Christian Toso, Pietro Majno, Jean-Paul Squifflet
This brief overview discusses the beneficial and deleterious effects of mTOR inhibitors on beta-cells, and how sirolimus- and everolimus-based immunosuppression have impacted on practices and outcomes of pancreas and islet transplantation. Sirolimus was the cornerstone of immunosuppressive regimens in islet transplantation at the turn of the millenium, but utilization of mTOR inhibitors has progressively decreased from >80% to <50% of islet transplant recipients in more recent years. For whole pancreas transplantation, mTOR inhibitors were used in approximately 20% of patients in the early 2000s, but this dropped over the years to <10% currently...
February 23, 2017: Transplantation
https://www.readbyqxmd.com/read/28230639/mammalian-target-of-rapamycin-inhibition-clinical-transplantation-liver
#11
Björn Nashan
The evidence base concerning use of mammalian target of rapamycin (mTOR) inhibitor therapy after liver transplantation is evolving rapidly, clarifying their benefits and disadvantages in different clinical scenarios. The H2304 trial showed that starting everolimus at 1 month posttransplant, with reduced tacrolimus, achieves a sustained improvement in renal function versus standard tacrolimus-based therapy, with at least equivalent immunosuppressive efficacy. Randomized studies evaluating early discontinuation of CNI therapy after introduction of an mTOR inhibitor consistently demonstrated a substantial improvement in renal function versus standard CNI therapy...
February 23, 2017: Transplantation
https://www.readbyqxmd.com/read/28230638/mtor-inhibition-cardiovascular-diseases-dyslipidemia-and-atherosclerosis
#12
Ammar Kurdi, Wim Martinet, Guido R Y De Meyer
Inhibitors of the mechanistic target of rapamycin (mTOR) have unique anti-atherosclerotic effects such as depletion of plaque macrophages, induction of autophagy and activation of cholesterol efflux. However, a common side effect of their use is dyslipidemia, a well-known risk factor for atherosclerosis. Indeed, mTOR inhibitors prevent lipid storage, increase LDL cholesterol levels and activate lipolysis. Although the net effect of mTOR inhibition seems favorable, the use of cholesterol lowering drugs to manage dyslipidemia remains the most recommended strategy...
February 23, 2017: Transplantation
https://www.readbyqxmd.com/read/28230637/mtor-inhibition-and-cardiovascular-diseases-cardiac-hypertrophy
#13
Ernesto Paoletti
Left ventricular hypertrophy (LVH) is highly prevalent in kidney transplant recipients, and is associated with poor clinical outcome. Immunosuppressive agents might affect LVH behavior after kidney transplantation. This review is an appraisal of available data regarding LVH in renal transplantation and especially of studies that evaluated LVH response to treatment. In particular, the role of mammalian target of rapamycin inhibitors adopted as immunosuppressive agents in kidney transplantation is reviewed in the light of recent studies that have shown LVH regression induced by this class of medications in kidney transplant recipients with posttransplant cardiomyopathy...
February 23, 2017: Transplantation
https://www.readbyqxmd.com/read/28230287/therapeutic-potential-of-targeting-pi3k-akt-pathway-in-treatment-of-colorectal-cancer-rational-and-progress
#14
Afsane Bahrami, Majid Khazaei, Malihe Hasanzadeh, Soodabeh ShahidSales, Mona Joudi Mashhad, Marjaneh Farazestanian, Hamid Reza Sadeghnia, Majid Rezayi, Mina Maftouh, Seyed Mahdi Hassanian, Amir Avan
PI3K/AKT/mTOR signaling pathway is one of the key dysregulated pathways in different tumor types, including colorectal cancer (CRC). Activation of this pathway is shown to be related with cellular transformation, tumor progression, cell survival and drug resistance. There is growing body of data evaluating the value of PI3K/AKT/mTOR inhibitors in CRC (e.g., BEZ235, NVP-BEZ235, OSI-027, everolimus, MK-2206, KRX-0401, BYL719 and BKM120). This report summarizes the current knowledge about PI3K/AKT pathway and its cross talk with ERK/MAPK and mTOR pathways with particular emphasis on the value of targeting this pathway as a potential therapeutic target in treatment of colorectal cancer...
February 23, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28229367/inhibition-of-mtor-pathway-by-rapamycin-decreases-p-glycoprotein-expression-and-spontaneous-seizures-in-pharmacoresistant-epilepsy
#15
Xiaosa Chi, Cheng Huang, Rui Li, Wei Wang, Mengqian Wu, Jinmei Li, Dong Zhou
The mammalian target of rapamycin (mTOR) has been demonstrated to mediate multidrug resistance in various tumors by inducing P-glycoprotein (P-gp) overexpression. Here, we investigated the correlation between the mTOR pathway and P-gp expression in pharmacoresistant epilepsy. Temporal cortex specimens were obtained from patients with refractory mesial temporal lobe epilepsy (mTLE) and age-matched controls who underwent surgeries at West China Hospital of Sichuan University between June 2014 and May 2015. We established a rat model of epilepsy kindled by coriaria lactone (CL) and screened pharmacoresistant rats (non-responders) using phenytoin...
February 22, 2017: Journal of Molecular Neuroscience: MN
https://www.readbyqxmd.com/read/28228706/the-pi3k-pathway-background-and-treatment-approaches
#16
REVIEW
Michael P Lux, Peter A Fasching, Michael G Schrauder, Alexander Hein, Sebastian M Jud, Claudia Rauh, Matthias W Beckmann
Two-thirds of all breast cancer patients with metastases have a hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative subtype. Endocrine therapy is the treatment of choice in these patients since in addition to its effectiveness it can also maintain the patients' quality of life over a longer term. However, 44-62% of postmenopausal patients with metastatic breast carcinoma have primary tamoxifen resistance. After 3-5 years, 30-40% of the patients receiving tamoxifen treatment develop secondary resistance...
December 2016: Breast Care
https://www.readbyqxmd.com/read/28228357/activation-of-mtor-i%C3%AE%C2%BAb-%C3%AE-nf-%C3%AE%C2%BAb-pathway-contributes-to-lps-induced-hypotension-and-inflammation-in-rats
#17
Meryem Temiz-Resitoglu, Sefika Pinar Kucukkavruk, Demet Sinem Guden, Pelin Cecen, Ayse Nihal Sari, Bahar Tunctan, Aysegul Gorur, Lulufer Tamer-Gumus, Cuneyt Kemal Buharalioglu, Kafait U Malik, Seyhan Sahan-Firat
Mammalian target of rapamycin (mTOR), a serine/threonine kinase plays an important role in various pathophysiological processes including cancer, metabolic diseases, and inflammation. Although mTOR participates in Toll-like receptor 4 signalling in different cell types, the role of this enzyme in sepsis pathogenesis and its effects on hypotension and inflammation in endotoxemic rats remains unclear. In this study we investigated the effects of mTOR inhibition on lipopolysaccharide (LPS)-induced changes on expressions and/or activities of ribosomal protein S6 (rpS6), an mTOR substrate, nuclear factor-κB (NF-κB) p65, inhibitor κB (IκB)-α, inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 with production of nitric oxide, peroxynitrite, prostacyclin, and tumor necrosis factor (TNF)-α and activity of myeloperoxidase (MPO), which results in hypotension and inflammation...
February 20, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28224235/oral-mucosal-changes-induced-by-anticancer-targeted-therapies-and-immune-checkpoint-inhibitors
#18
REVIEW
Emmanuelle Vigarios, Joel B Epstein, Vincent Sibaud
Development of biological targeted therapies and immune checkpoint inhibitors has redefined the treatment for many cancers; however, the increasing use of new protocols has led to physicians observing a new spectrum of toxicities. To date, oral adverse events induced by these new anticancer therapies have been mainly reported using nonspecific terminology ("stomatitis," "mucosal inflammation," "mucositis") and remain poorly characterized, with the exception of mammalian target of rapamycin (mTOR) inhibitor-associated stomatitis...
February 22, 2017: Supportive Care in Cancer: Official Journal of the Multinational Association of Supportive Care in Cancer
https://www.readbyqxmd.com/read/28222438/microrna-29b-inhibits-angiogenesis-by-targeting-vegfa-through-the-mapk-erk-and-pi3k-akt-signaling-pathways-in-endometrial-carcinoma
#19
Hong-Xia Chen, Xiao-Xia Xu, Bu-Zhen Tan, Zhi Zhang, Xiao-Dong Zhou
OBJECTIVE: The purpose of this study is to explore the effects of microRNA-29b (miR-29b) regulating MAPK/ERK and PI3K/Akt signaling pathways on angiogenesis in endometrial carcinoma (EC) by targeting VEGFA. METHODS: Between February 2013 and April 2015, 126 EC patients admitted to the Second Affiliated Hospital of Nanchang University were randomly selected, with 126 EC tissues and the corresponding adjacent normal tissues collected after surgery. The human EC cell lines RL-95-2 and HEC-1-B and human endometrial cells were assigned to the normal group (human endometrial cells), the blank group (untransfected RL-95-2 or HEC-1-B cells), the pMIR-control group (RL-95-2 or HEC-1-B cells transfected with an empty vector), the pMIR-miR-29b group (RL-95-2 or HEC-1-B cells transfected with the miR-29b plasmid), LNA-control group (RL-95-2 or HEC-1-B cells transfected with an oligonucleotide inhibitors control), the LNA-miR-29b inhibitors group (RL-95-2 or HEC-1-B cells transfected with miRCURY LNATM miR-29b inhibitors), the LNA-miR-29b inhibitors + PD98059 group (RL-95-2 or HEC-1-B cells transfected with miRCURY LNATM miR-29b inhibitors and PD98059, an inhibitor of the MAPK/ERK signaling pathway) and the LNA-miR-29b inhibitors + wortmannin group (RL-95-2 or HEC-1-B cells transfected with miRCURY LNATM miR-29b inhibitors and wortmannin, an inhibitor of the PI3K/Akt signaling pathway)...
February 20, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28222404/glycemic-control-in-patients-with-insulinoma
#20
REVIEW
Agata Matej, Hanna Bujwid, Jakub Wroński
Insulinoma is the most common neuroendocrine tumor of the pancreas. Surgical management of insulinomas is considered to be the only curative method. However, effective glycemic control preoperatively and in unresectable insulinomas remains a significant issue. Hyperinsulinism, occurring as a result of the hormone-secreting tumor, leads to life-threatening hypoglycemia episodes which require urgent medical treatment. This article discusses current management of hypoglycemia in insulinoma patients, including: education and lifestyle modifications, pharmacotherapy (diazoxide, somatostatin analogs, mTOR inhibitor - everolimus), cytoreductive methods and continuous glucose monitoring systems...
October 2016: Hormones: International Journal of Endocrinology and Metabolism
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