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https://www.readbyqxmd.com/read/28806782/the-use-of-18f-fluoro-deoxy-glucose-positron-emission-tomography-18f-fdg-pet-as-a-non-invasive-pharmacodynamic-biomarker-to-determine-the-minimally-pharmacologically-active-dose-of-azd8835-a-novel-pi3k%C3%AE-inhibitor
#1
Juliana Maynard, Sally-Ann Emmas, Francois-Xavier Ble, Herve Barjat, Emily Lawrie, Urs Hancox, Urszula M Polanska, Alison Pritchard, Kevin Hudson
BACKGROUND: The phosphatidyl inositol 3 kinase (PI3K), AKT and mammalian target of rapamycin (mTOR) signal transduction pathway is frequently de-regulated and activated in human cancer and is an important therapeutic target. AZD8835 is a PI3K inhibitor, with selectivity against PI3K α and δ isoforms, which is currently in Phase 1 clinical trials. 18F-Fluoro-deoxy-glucose positron emission tomography (18F-FDG PET) is a non-invasive pharmacodynamic imaging biomarker that has become an integral part of drug development...
2017: PloS One
https://www.readbyqxmd.com/read/28806703/nox4-mediated-ros-production-induces-apoptotic-cell-death-via-down-regulation-of-c-flip-and-mcl-1-expression-in-combined-treatment-with-thioridazine-and-curcumin
#2
Seung Un Seo, Tae Hwan Kim, Dong Eun Kim, Kyoung-Jin Min, Taeg Kyu Kwon
Thioridazine is known to have anti-tumor effects by inhibiting PI3K/Akt signaling, which is an important signaling pathway in cell survival. However, thioridazine alone does not induce apoptosis in head and neck squamous cell carcinoma (AMC-HN4), human breast carcinoma (MDA-MB231), and human glioma (U87MG) cells. Therefore, we investigated whether combined treatment with thioridazine and curcumin induces apoptosis. Combined treatment with thioridazine and curcumin markedly induced apoptosis in cancer cells without inducing apoptosis in human normal mesangial cells and human normal umbilical vein cells (EA...
August 9, 2017: Redox Biology
https://www.readbyqxmd.com/read/28805297/mesenchymal-stem-cells-deliver-exogenous-mir-21-via-exosomes-to-inhibit-nucleus-pulposus-cell-apoptosis-and-reduce-intervertebral-disc-degeneration
#3
Xiaofei Cheng, Guoying Zhang, Liang Zhang, Ying Hu, Kai Zhang, Xiaojiang Sun, Changqing Zhao, Hua Li, Yan Michael Li, Jie Zhao
Although mesenchymal stem cells (MSCs) transplantation into the IVD (intervertebral disc) may be beneficial in inhibiting apoptosis of nucleus pulposus cells (NPCs) and alleviating IVD degeneration, the underlying mechanism of this therapeutic process has not been fully explained. The purpose of this study was to explore the protective effect of MSC-derived exosomes (MSC-exosomes) on NPC apoptosis and IVD degeneration and investigate the regulatory effect of miRNAs in MSC-exosomes and associated mechanisms for NPC apoptosis...
August 14, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28804726/low-dose-of-lipopolysaccharide-pretreatment-preventing-subsequent-endotoxin-induced-uveitis-is-associated-with-pi3k-akt-pathway
#4
Nan Zhang, Shuo Yu, Xinli Liu, Hong Lu
PURPOSE: To explore the effects of LPS pretreatment on endotoxin-induced uveitis and PI3K/AKT pathway. METHODS: Endotoxin-induced uveitis was induced by a single subcutaneous injection of 200 μg LPS. For the endotoxin tolerance group, induction of EIU was preceded by daily subcutaneous injection of 0.1 mg/kg LPS for five days. Clinical scores were graded at 24 h after EIU under a slit lamp microscope. HE stain was performed to observe the histopathology. Aqueous humor TNF-α concentration was quantified with enzyme-linked immunosorbent assay...
2017: Journal of Immunology Research
https://www.readbyqxmd.com/read/28804691/combination-of-celecoxib-celebrex-%C3%A2-and-cd19-car-redirected-ctl-immunotherapy-for-the-treatment-of-b-cell-non-hodgkin-s-lymphomas
#5
REVIEW
Tam Nm Dinh, Alexandra S Onea, Ali R Jazirehi
The nonsteroidal anti-inflammatory drug (NSAID) Celecoxib (Celebrex(®)) received Food and Drug Administration (FDA) approval in 1998 for treatment of osteoarthritis and rheumatoid arthritis, and in recent years, its use has been extended to various types of malignancies, such as breast, colon, and urinary cancers. To maintain the survival of malignant B cells, non-Hodgkin's Lymphoma (NHL) is highly dependent on inflammatory microenvironment, and is inhibited by celecoxib. Celecoxib hinders tumor growth interacting with various apoptotic genes, such as cyclooxygenase-2 (Cox-2), B-cell lymphoma 2 (Bcl-2) family, phosphor-inositide-3 kinase/serine-threonine-specific protein kinase (PI3K/Akt), and inhibitors of apoptosis proteins (IAP) family...
2017: American Journal of Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/28803046/design-synthesis-and-biological-evaluation-of-novel-pyrazolochalcones-as-potential-modulators-of-pi3k-akt-mtor-pathway-and-inducers-of-apoptosis-in-breast-cancer-cells
#6
Anver Basha Shaik, Garikapati Koteswara Rao, G Bharath Kumar, Nibeditha Patel, Vangala Santhosh Reddy, Irfan Khan, Sunitha Rani Routhu, C Ganesh Kumar, Immadi Veena, Kunta Chandra Shekar, Madan Barkume, Shailesh Jadhav, Aarti Juvekar, Jyoti Kode, Manika Pal-Bhadra, Ahmed Kamal
Cancer has been established as the "Emperor of all maladies". In recent years, medicinal chemistry has focused on identifying novel anti-cancer compounds; though discovery of these compounds appears to be a herculean task. In present study, we synthesized forty pyrazolochalcone conjugates and explored their cytotoxic activity against a panel of sixty cancer cell lines. Fifteen conjugates of the series showed excellent growth inhibition (13b-e, 13h-j, 14c-d, 15 a, 15 c-d, 16b, 16d and 18f; GI50 for MCF-7: 0...
July 25, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28802226/taraxerol-a-pentacyclic-triterpenoid-from-abroma-augusta-leaf-attenuates-diabetic-nephropathy-in-type-2-diabetic-rats
#7
Ritu Khanra, Niloy Bhattacharjee, Tarun K Dua, Ashis Nandy, Achintya Saha, Jatin Kalita, Prasenjit Manna, Saikat Dewanjee
Persistent hyperglycaemia coupled with inflammation plays an important role in the pathogenesis of diabetic nephropathy (DN). Present study examined the therapeutic potential of taraxerol isolated from the methanol extract of Abroma augusta leaf against DN using rodent model of type 2 diabetes (T2D). T2D was experimentally induced by high fat diet and a single low-single dose of streptozotocin (35mg/kg, i.p.). Accumulation of serum creatinine, urea, and uric acid, activation of lactate dehydrogenase and creatinin kinase, and release of urinary albumin represented the glomerular damage and the progression of nephropathy in T2D rats...
August 9, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28801972/brief-report-a-differential-transcriptomic-profile-of-ex-vivo-expanded-adult-human-hematopoietic-stem-cells-empowers-them-for-engraftment-better-than-their-surface-phenotype
#8
Nikoletta Psatha, Grigorios Georgolopoulos, Susan Phelps, Thalia Papayannopoulou
Transplantation of small cord blood (CB) units, or of autologous ex vivo-genetically modified adult hematopoietic stem cells (HSC), face the common challenge of suboptimal HSC doses for infusion and impaired engraftment of the transplanted cells. Ex vivo expansion of HSCs, using either cell-based coculture approaches or especially small molecules have been successfully tested mainly in CB and in prolonged cultures. Here, we explored whether innovative combinations of small molecules can sufficiently, after short culture, expand adult HSCs while retaining their functionality in vivo...
August 11, 2017: Stem Cells Translational Medicine
https://www.readbyqxmd.com/read/28801592/dietary-arginine-affects-the-insulin-signaling-pathway-glucose-metabolism-and-lipogenesis-in-juvenile-blunt-snout-bream-megalobrama-amblycephala
#9
Hualiang Liang, Habte-Michael Habte-Tsion, Xianping Ge, Mingchun Ren, Jun Xie, Linghong Miao, Qunlan Zhou, Yan Lin, Wenjing Pan
This study evaluated the mechanisms governing insulin resistance, glucose metabolism and lipogenesis in juvenile fish fed with graded levels of dietary arginine. The results showed that, compared with the control group (0.87%), 2.31% dietary arginine level resulted in the upregulation of the relative gene expression of IRS-1, PI3K and Akt in the insulin signaling pathway, while 2.70% dietary arginine level led to inhibition of these genes. 1.62% dietary arginine level upregulated glycolysis by increasing GK mRNA level; 2...
August 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28800863/targeting-pi3k-akt-pathway-in-triple-negative-breast-cancer
#10
Suzette Delaloge, Louise DeForceville
No abstract text is available yet for this article.
August 8, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28800861/ipatasertib-plus-paclitaxel-versus-placebo-plus-paclitaxel-as-first-line-therapy-for-metastatic-triple-negative-breast-cancer-lotus-a-multicentre-randomised-double-blind-placebo-controlled-phase-2-trial
#11
Sung-Bae Kim, Rebecca Dent, Seock-Ah Im, Marc Espié, Sibel Blau, Antoinette R Tan, Steven J Isakoff, Mafalda Oliveira, Cristina Saura, Matthew J Wongchenko, Amy V Kapp, Wai Y Chan, Stina M Singel, Daniel J Maslyar, José Baselga
BACKGROUND: The oral AKT inhibitor ipatasertib is being investigated in cancers with a high prevalence of PI3K/AKT pathway activation, including triple-negative breast cancer. The LOTUS trial investigated the addition of ipatasertib to paclitaxel as first-line therapy for triple-negative breast cancer. METHODS: In this randomised, placebo-controlled, double-blind, phase 2 trial, women aged 18 years or older with measurable, inoperable, locally advanced or metastatic triple-negative breast cancer previously untreated with systemic therapy were recruited from 44 hospitals in South Korea, the USA, France, Spain, Taiwan, Singapore, Italy, and Belgium...
August 8, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28800786/knockdown-of-long-noncoding-rna-linc0000125-suppresses-cellular-proliferation-and-invasion-in-glioma-cells-by-regulating-mir-4775
#12
Zhankun Zhu, Jinhua Dai, Yufeng Liao, Jianbo Ma, Wei Zhou
Long noncoding RNAs (lncRNAs) play an important role in various biological properties of glioma cells. Herein, we aimedto elucidate the function and the possible molecular mechanisms of long intergenic non-coding RNA 152 (LINC00152) in glioma cells. Relative expressions of LINC00152, miR-4775 and CDK6 in U-118 MG cells were regulated by transfections. Thereafter, cell viability, migration, invasion and apoptosis were analyzed by CCK8, Transwell and flow cytometry assays. Dual-luciferase reporter assay was conducted to validate the target genes of LINC00152 and miR-4775...
August 11, 2017: Oncology Research
https://www.readbyqxmd.com/read/28800461/design-synthesis-and-biological-evaluation-of-novel-3-substituted-imidazo-1-2-a-pyridine-and-quinazolin-4-3h-one-derivatives-as-pi3k%C3%AE-inhibitors
#13
Yan-Hua Fan, Wei Li, Dan-Dan Liu, Meng-Xuan Bai, Hong-Rui Song, Yong-Nan Xu, SangKook Lee, Zhi-Peng Zhou, Jian Wang, Huai-Wei Ding
Phosphatidylinositol 3-kinase (PI3K) is a pivotal regulator of intracellular signaling pathways and considered as a promising target in the development of a therapeutic treatment of cancer. Among the different PI3K subtypes, the PIK3CA gene encoding PI3K p110α is frequently mutated and overexpressed in majority of human cancers. Therefore, the inhibition of PI3Kα has been considered to be an efficient approach for the treatment of cancer. In this study, two series compounds containing hydrophilic group in imidazo[1,2-a]pyridine and quinazolin-4(3H)-one were synthesized and their antiproliferative activities against five cancer cell lines, including HCT-116, SK-HEP-1, MDA-MB-231, SNU638 and A549, were evaluated...
August 1, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28800359/the-selective-pi3k%C3%AE-inhibitor-byl719-as-a-novel-therapeutic-option-for-neuroendocrine-tumors-results-from-multiple-cell-line-models
#14
Svenja Nölting, Jakob Rentsch, Helma Freitag, Katharina Detjen, Franziska Briest, Markus Möbs, Victoria Weissmann, Britta Siegmund, Christoph J Auernhammer, Elke Tatjana Aristizabal Prada, Michael Lauseker, Ashley Grossman, Samantha Exner, Christian Fischer, Carsten Grötzinger, Jörg Schrader, Patricia Grabowski
BACKGROUND/AIMS: The therapeutic options for metastatic neuroendocrine tumors (NETs) are limited. As PI3K signaling is often activated in NETs, we have assessed the effects of selective PI3Kp110α inhibition by the novel agent BYL719 on cell viability, colony formation, apoptosis, cell cycle, signaling pathways, differentiation and secretion in pancreatic (BON-1, QGP-1) and pulmonary (H727) NET cell lines. METHODS: Cell viability was investigated by WST-1 assay, colony formation by clonogenic assay, apoptosis by caspase3/7 assay, the cell cycle by FACS, cell signaling by Western blot analysis, expression of chromogranin A and somatostatin receptors 1/2/5 by RT-qPCR, and chromogranin A secretion by ELISA...
2017: PloS One
https://www.readbyqxmd.com/read/28800073/electronegative-low-density-lipoprotein-l5-impairs-viability-and-ngf-induced-neuronal-differentiation-of-pc12-cells-via-lox-1
#15
Jiz-Yuh Wang, Chiou-Lian Lai, Ching-Tien Lee, Chen-Yen Lin
There have been striking associations of cardiovascular diseases (e.g., atherosclerosis) and hypercholesterolemia with increased risk of neurodegeneration including Alzheimer's disease (AD). Low-density lipoprotein (LDL), a cardiovascular risk factor, plays a crucial role in AD pathogenesis; further, L5, a human plasma LDL fraction with high electronegativity, may be a factor contributing to AD-type dementia. Although L5 contributing to atherosclerosis progression has been studied, its role in inducing neurodegeneration remains unclear...
August 11, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28800035/the-anti-malarial-drug-artesunate-attenuates-cardiac-injury-in-a-rodent-model-of-myocardial-infarction
#16
Areeg I Khan, Amar Kapoor, Jianmin Che, Lukas Martin, Mara Rogazzo, Thomas Mercier, Laurent Decosterd, Massimo Collino, Christoph Thiemermann
Ischaemic heart disease remains the leading cause of morbidity and mortality in the Western world. Artesunate is the WHO-recommended drug of choice for complicated malaria (with organ failure). The administration of high doses of artesunate is safe in healthy volunteers (up to 8 mg/kg i.v) and patients with severe malaria (2.4 mg/kg i.v). We investigated the effects of artesunate (1 mg/kg) or its active metabolite dihydroartemisinin (DHA; 0.1 mg/kg) in a model of transient myocardial ischaemia/reperfusion (I/R) and evaluated the mechanism of action of the observed cardioprotective effects of artesunate and DHA...
August 9, 2017: Shock
https://www.readbyqxmd.com/read/28798142/accumulation-of-smooth-muscle-22%C3%AE-protein-accelerates-senescence-of-vascular-smooth-muscle-cells-via-stabilization-of-p53-in-vitro-and-in-vivo
#17
Sui-Bing Miao, Xiao-Li Xie, Ya-Juan Yin, Li-Li Zhao, Fan Zhang, Ya-Nan Shu, Rong Chen, Peng Chen, Li-Hua Dong, Yan-Ling Lin, Pin Lv, Dan-Dan Zhang, Xi Nie, Zhen-Ying Xue, Mei Han
OBJECTIVE: Smooth muscle (SM) 22α, an actin-binding protein, displays an upregulated expression as a marker during cellular senescence. However, the causal relationship between SM22α and senescence is poorly understood. This study aimed to investigate the role of SM22α in angiotensin II (Ang II)-induced senescence of vascular smooth muscle cells (VSMCs). APPROACH AND RESULTS: We prepared a model of VSMC senescence induced by Ang II and found that the expression of SM22α in VSMCs was increased in response to chronic Ang II treatment...
August 10, 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28797845/the-hsp90-inhibitor-nvp-auy922-attenuates-intrinsic-pi3k-inhibitor-resistance-in-kras-mutant-non-small-cell-lung-cancer
#18
Kang-Seo Park, Hannah Yang, Junyoung Choi, Seyoung Seo, Deokhoon Kim, Chang Hoon Lee, Hanwool Jeon, Sang-We Kim, Dae Ho Lee
More than 25% of non-small cell lung cancers (NSCLCs) carry mutations in KRAS, one of the most common oncogenic drivers in this disease. KRAS-mutant NSCLC responds poorly to currently available therapies; therefore, novel treatment strategies are needed. Here, we describe a particularly promising targeted therapeutic strategy against KRAS mutation-harboring NSCLC intrinsically resistant to treatment by PI3K inhibition. We found that intrinsic resistance to PI3K inhibition derived from RAF/MEK/ERK and RSK activation, bypassing blockage of the PI3K/AKT/mTOR pathway...
August 7, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28797056/anaplasma-phagocytophilum-infection-modulates-expression-of-megakaryocyte-cell-cycle-genes-through-phosphatidylinositol-3-kinase-signaling
#19
Supreet Khanal, Hameeda Sultana, John D Catravas, Jason A Carlyon, Girish Neelakanta
Anaplasma phagocytophilum, the agent of human granulocytic anaplasmosis infects neutrophils and other cells from hematopoietic origin. Using human megakaryocytic cell line, MEG-01, we show that expression of cell cycle genes in these cells are altered upon A. phagocytophilum infection. Expression of several cell cycle genes in MEG-01 cells was significantly up regulated at early and then down regulated at later stages of A. phagocytophilum infection. Lactate dehydrogenase (LDH) assays revealed reduced cellular cytotoxicity in MEG-01 cells upon A...
2017: PloS One
https://www.readbyqxmd.com/read/28796787/the-quinic-acid-derivative-kz-41-prevents-glucose-induced-caspase-3-activation-in-retinal-endothelial-cells-through-an-igf-1-receptor-dependent-mechanism
#20
Hui He, Rebecca L Weir, Jordan J Toutounchian, Jayaprakash Pagadala, Jena J Steinle, Jerome Baudry, Duane D Miller, Charles R Yates
Retinal microaneurysms, an early disease manifestation of diabetic retinopathy, are associated with retinal endothelial cell (REC) death and macular edema. We previously demonstrated that a quinic acid (QA) analog, KZ-41, promoted REC survival by blunting stress-induced p38 MAPK activation. Herein, we sought to expand our understanding of the pro-survival signal transduction pathways actuated by KZ-41. Using human RECs exposed to high glucose (25 mM, 72 hours), we demonstrated that KZ-41 blocks caspase-3 activation by triggering phosphorylation of the PI3K regulatory subunit (p85; Tyr458) and its downstream target Akt (Ser473)...
2017: PloS One
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