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Pi3kinase inhibitor

Kenneth D'Souza, Daniel A Kane, Mohamed Touaibia, Erin E Kershaw, Thomas Pulinilkunnil, Petra C Kienesberger
Autotaxin (ATX) is an adipokine that generates the bioactive lipid, lysophosphatidic acid. Despite recent studies implicating adipose-derived ATX in metabolic disorders including obesity and insulin resistance, the nutritional and hormonal regulation of ATX in adipocytes remains unclear. The current study examined the regulation of ATX in adipocytes by glucose and insulin and the role of ATX in adipocyte metabolism. Induction of insulin resistance in adipocytes with high glucose and insulin concentrations increased ATX secretion, whereas coincubation with the insulin sensitizer, rosiglitazone, prevented this response...
April 1, 2017: Endocrinology
Youssef Aissouni, Abderrahim El Guerrab, Al Mahdy Hamieh, Jérémy Ferrier, Maryse Chalus, Diane Lemaire, Stéphanie Grégoire, Monique Etienne, Alain Eschalier, Denis Ardid, Eric Lingueglia, Fabien Marchand
Chronic pain is associated with anxiety and depression episodes. The amygdala plays a key role in the relationship between emotional responses and chronic pain. Here, we investigated the role of Acid-Sensing Ion Channels 1a within the basolateral amygdala (BLA), in pain and associated anxiety in a rat model of monoarthritis (MoAr). Administration within the BLA of PcTx1 or mambalgin-1, two specific inhibitors of ASIC1a-containing channels significantly inhibited pain and anxiety-related behaviours in MoAr rats...
March 2, 2017: Scientific Reports
U A Matulonis, G M Wulf, W T Barry, M Birrer, S N Westin, S Farooq, K M Bell-McGuinn, E Obermayer, C Whalen, T Spagnoletti, W Luo, H Liu, R C Hok, C Aghajanian, D B Solit, G B Mills, B S Taylor, H Won, M F Berger, S Palakurthi, J Liu, L C Cantley, E Winer
Background: Based upon preclinical synergy in murine models, we carried out a phase I trial to determine the maximum tolerated dose (MTD), toxicities, pharmacokinetics, and biomarkers of response for the combination of BKM120, a PI3K inhibitor, and olaparib, a PARP inhibitor. Patients and methods: Olaparib was administered twice daily (tablet formulation) and BKM120 daily on a 28-day cycle, both orally. A 3 + 3 dose-escalation design was employed with the primary objective of defining the combination MTD, and secondary objectives were to define toxicities, activity, and pharmacokinetic profiles...
March 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
M Fonteneau, D Filliol, P Anglard, K Befort, P Romieu, J Zwiller
DNA methylation is a major epigenetic process which regulates the accessibility of genes to the transcriptional machinery. In the present study, we investigated whether modifying the global DNA methylation pattern in the brain would alter cocaine intake by rats, using the cocaine self-administration test. The data indicate that treatment of rats with the DNA methyltransferase inhibitors 5-aza-2'-deoxycytidine (dAZA) and zebularine enhanced the reinforcing properties of cocaine. To obtain some insights about the underlying neurobiological mechanisms, a genome-wide methylation analysis was undertaken in the prefrontal cortex of rats self-administering cocaine and treated with or without dAZA...
October 20, 2016: Genes, Brain, and Behavior
L Zhang, M Kolaj, L P Renaud
In rat paraventricular thalamic nucleus (PVT) neurons, activation of low-threshold calcium (Ca(2+)) channels triggers a low-threshold spike (LTS) which may be followed by slow afterpotentials that can dramatically influence action potential patterning. Using gluconate-based internal recording solutions, we investigated the properties of a LTS-induced slow afterdepolarization (sADP) observed in a subpopulation of PVT neurons recorded in brain slice preparations. This LTS-induced sADP required T-type Ca(2+) channel opening, exhibited variable magnitudes between neurons and a voltage dependency with a maximum near -50 mV...
May 13, 2016: Neuroscience
Sally E Dickinson, Jaroslav Janda, Jane Criswell, Karen Blohm-Mangone, Erik R Olson, Zhonglin Liu, Christy Barber, Emanuel F Petricoin, Valerie S Calvert, Janine Einspahr, Jesse E Dickinson, Steven P Stratton, Clara Curiel-Lewandrowski, Kathylynn Saboda, Chengcheng Hu, Ann M Bode, Zigang Dong, David S Alberts, G Timothy Bowden
The PI3Kinase/Akt/mTOR pathway has important roles in cancer development for multiple tumor types, including UV-induced nonmelanoma skin cancer. Immunosuppressed populations are at increased risk of aggressive cutaneous squamous cell carcinoma (SCC). Individuals who are treated with rapamycin (sirolimus, a classical mTOR inhibitor) have significantly decreased rates of developing new cutaneous SCCs compared with those that receive traditional immunosuppression. However, systemic rapamycin use can lead to significant adverse events...
March 2016: Cancer Prevention Research
Augusto Carducci, Gaia Scafetta, Camilla Siciliano, Roberto Carnevale, Paolo Rosa, Andrea Coccia, Giorgio Mangino, Antonella Bordin, Enzo Maria Vingolo, Luca Pierelli, Eugenio Lendaro, Giuseppe Ragona, Giacomo Frati, Elena De Falco
Tenon's fibroblasts (TFs), widely employed as in vitro model for many ophthalmological studies, are routinely cultured with FBS. Platelet Lysate (PL), a hemoderivate enriched with growth factors and cytokines has been largely tested in several clinical applications and as substitute of FBS in culture. Here, we investigate whether PL can exert biological effects on TF populations similarly to other cell types. Results show that PL significantly enhances cell proliferation and migration vs. FBS, without influencing cell size/granularity...
2016: Frontiers in Bioscience (Elite Edition)
Erin Zekas, Eric R Prossnitz
BACKGROUND: Estrogen (17β-estradiol) promotes the survival and proliferation of breast cancer cells and its receptors represent important therapeutic targets. The cellular actions of estrogen are mediated by the nuclear estrogen receptors ERα and ERβ as well as the 7-transmembrane spanning G protein-coupled estrogen receptor (GPER). We previously reported that estrogen activates the phosphoinositide 3-kinase (PI3Kinase) pathway via GPER, resulting in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) production within the nucleus of breast cancer cells; however, the mechanisms and consequences of this activity remained unclear...
October 15, 2015: BMC Cancer
Haihua Zhang, Robrecht Thoonen, Vincent Yao, Emmanuel S Buys, John Popovich, Yan Ru Su, Thomas J Wang, Marielle Scherrer-Crosbie
Human studies suggest that insulin resistance and obesity are associated with a decrease in B-type natriuretic peptide (BNP) plasma concentrations. The objective of the study was to gain insights into the mechanisms involved in the association between insulin resistance and decreased BNP plasma concentrations. Mice fed a high-fat, high-fructose (HFHF) diet for 4 weeks developed mild obesity and systemic insulin resistance. Elevated plasma concentrations of insulin, glucose and triglycerides were noted. The HFHF diet was also associated with myocardial insulin resistance, characterized by an impaired response of the phosphoinositide 3-kinase-AKT (PI3K-AKT) pathway to insulin in the left ventricle...
January 2016: Experimental Physiology
Vijaya Lakshmi Bodiga, Sandhya Thokala, Praveen Kumar Vemuri, Sreedhar Bodiga
Heart tissue becomes zinc-depleted and the capacity to mobilize labile zinc is diminished, indicating zinc dyshomeostasis during ischemia/reperfusion (I/R). Apparently, zinc pyrithione restores the basal zinc levels during I/R and prevents apoptosis by activating phosphatidyl inositol-3-kinase/Akt and targeting mitochondrial permeability transition. Receptor tyrosine kinases of the ErbB family (ErbB1 to ErbB4) are cell surface proteins that can regulate cell growth, proliferation and survival. Previous studies have shown that zinc pyrithione-induced activation of PI3kinase/Akt requires ErbB2 expression...
December 2015: Journal of Inorganic Biochemistry
Yan Xu, Leslie R Morse, Raquel Assed Bezerra da Silva, Dianhua Wang, Ricardo A Battaglino
Reactive oxygen species (ROS) play a central role in estrogen deficiency-induced bone loss. We previously identified and characterized a novel member of the Peroxiredoxin (PRX) like 2 family that we called PAMM: Peroxiredoxin Activated in M-CSF stimulated Monocytes, a redox regulatory protein that modulates osteoclast differentiation in vitro. In this study, we report increased PAMM expression in H2O2-treated cells and in bones from ovariectomized (OVX) mice 4 weeks after surgery, models for oxidative stress in vitro and in vivo, respectively...
December 2015: Redox Biology
Peter J Barnes
There is an urgent need to develop more effective therapies for chronic obstructive pulmonary disease (COPD) that target the underlying inflammatory disease process. Current therapies with long-acting bronchodilators and inhaled corticosteroids fail to prevent either disease progression or mortality, as they do not suppress the underlying inflammation. With better understanding of the inflammatory and destructive process in the pathophysiology of COPD, several new therapeutic targets have been identified. Several mediator antagonists or inhibitors tested in COPD have so far been disappointing...
August 2015: Seminars in Respiratory and Critical Care Medicine
Tetsuya Yoshimoto, Tsuyoshi Fujita, Mikihito Kajiya, Shinji Matsuda, Kazuhisa Ouhara, Hideki Shiba, Hidemi Kurihara
Periodontitis is the most prevalent infectious disease caused by periodontopathic bacteria and is also a chronic inflammatory disease. Gingival crevicular fluid (GCF) is an inflammatory exudate that seeps into the gingival crevices or periodontal pockets around teeth with inflamed gingiva, and contains various materials including leukocytes and cytokines. Since gingival epithelial cells, which form a barrier against bacterial challenges, are affected by GCF, cytokines or other materials contained within GCF are engaged in the maintenance and disruption of the epithelial barrier...
September 2015: Cytokine
S Moulder, T Helgason, F Janku, J Wheler, J Moroney, D Booser, C Albarracin, P K Morrow, J Atkins, K Koenig, M Gilcrease, R Kurzrock
BACKGROUND: Mesenchymal/metaplastic breast cancers (MpBCs) are often triple-negative (TNBC), and chemo-refractory, and can harbor phosphoinositide 3-kinase (PI3kinase) alterations; thus, therapy with mTor inhibitors may demonstrate activity. PATIENTS AND METHODS: Patients with mesenchymal/MpBC treated with temsirolimus-based regimens were evaluated. Mutational analyses [polymerase chain reaction (PCR)-based DNA sequencing method, mass spectrometric detection (Sequenom MassARRAY), or next-generation sequencing] as well as loss of phosphatase and tensin homolog (PTEN) (immunohistochemistry) were performed (archived tissue when available)...
July 2015: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Natalia Calvo, María Julia Martín, Ana Russo de Boland, Claudia Gentili
Parathyroid hormone-related peptide (PTHrP) is distributed in most fetal and adult tissues, and its expression correlates with the severity of colon carcinoma. Recently we obtained evidence that in Caco-2 cells, a cell line from human colorectal adenocarcinoma, exogenous PTHrP increases the number of live cells, via ERK1/2, p38 MAPK, and PI3-kinase and induces the expression of cyclin D1, a cell cycle regulatory protein. In this study, we further investigated the role of PTHrP in the regulation of the cell cycle progression in these intestinal cells...
August 2014: Biochemistry and Cell Biology, Biochimie et Biologie Cellulaire
Mikihito Kajiya, Kei Takeshita, Mizuho Kittaka, Shinji Matsuda, Kazuhisa Ouhara, Katsuhiro Takeda, Takashi Takata, Masae Kitagawa, Tsuyoshi Fujita, Hideki Shiba, Hidemi Kurihara
Brain-derived neurotrophic factor (BDNF) activates its receptor TrkB, and promotes neuronal survival, differentiation, and synaptic functions. Furthermore, we have revealed that BDNF can also regulate cementoblast differentiation and cellular survival via TrkB-ERK/Akt signaling cascade, which, in turn, results in the induction of periodontal tissue regeneration. Recently, using in silico screening with a BDNF loop-domain pharmacophore, a small molecule BDNF mimetic, called LM22A-4 that can facilitate TrkB signaling in hippocampal neurons to prevent cell death, was identified...
April 2014: International Immunopharmacology
Jasmine El Andalousi, Yuan Li, Madhu B Anand-Srivastava
Vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) exhibit hyperproliferation and overexpression of cell cycle proteins. We earlier showed that small peptide fragments of cytoplasmic domain of natriuretic receptor-C (NPR-C) attenuate vasoactive peptide-induced hyperproliferation of VSMC. The present study investigated if C-ANP4-23, a specific agonist of NPR-C, could attanuate the hyperproliferation of VSMC from SHR by inhibiting the overexpression of cell cycle proteins and examine the underlying signaling pathways contributing to this inhibition...
2013: PloS One
Thao M Nguyen, Agnes Arthur, John D Hayball, Stan Gronthos
Mesenchymal stromal/stem cells (MSC) express the contact-dependent erythropoietin-producing hepatocellular (Eph) receptor tyrosine kinase family and their cognate ephrin ligands, which are known to regulate thymocyte maturation and selection, T-cell transendothelial migration, activation, co-stimulation, and proliferation. However, the contribution of Eph/ephrin molecules in mediating human MSC suppression of activated T-cells remains to be determined. In the present study, we showed that EphB2 and ephrin-B2 are expressed by ex vivo expanded MSC, while the corresponding ligands, ephrin-B1 and EphB4, respectively, are highly expressed by T-cells...
October 15, 2013: Stem Cells and Development
Kerstin Maria Kampa-Schittenhelm, Michael Charles Heinrich, Figen Akmut, Katharina Henriette Rasp, Barbara Illing, Hartmut Döhner, Konstanze Döhner, Marcus Matthias Schittenhelm
BACKGROUND: Dysregulation of the PI3Kinase/AKT pathway is involved in the pathogenesis of many human malignancies. In acute leukemia, the AKT pathway is frequently activated, however mutations in the PI3K/AKT pathway are uncommon. In some cases, constitutive AKT activation can be linked to gain-of-function tyrosine kinase (TK) mutations upstream of the PI3K/AKT pathway. Inhibitors of the PI3K/AKT pathway are attractive candidates for cancer drug development, but so far clinical efficacy of PI3K inhibitors against various neoplasms has been moderate...
2013: Molecular Cancer
Hussein Ajj, Amand Chesnel, Sophie Pinel, François Plenat, Stephane Flament, Helene Dumond
Long chain alkylphenols are man-made compounds still present in industrial and agricultural processes. Their main use is domestic and they are widespread in household products, cleansers and cosmetics, leading to a global environmental and human contamination. These molecules are known to exert estrogen-like activities through binding to classical estrogen receptors. In vitro, they can also interact with the G-protein coupled estrogen receptor. Testicular germ cell tumor etiology and progression are proposed to be stimulated by lifelong estrogeno-mimetic exposure...
2013: PloS One
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