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https://www.readbyqxmd.com/read/28342965/effects-of-i2-imidazoline-receptor-ir-alkylating-bu99006-in-the-mouse-brain-upregulation-of-nischarin-i1-ir-and-%C3%AE-opioid-receptor-proteins-and-modulation-of-associated-signalling-pathways
#1
Benjamin Keller, Jesús A García-Sevilla
5-isothiocyanato-2-benzofuranyl-2-imidazoline (BU99006) was shown to selectively and irreversibly bind to I2-imidazoline receptors (IRs) in vitro and in vivo, but cell signalling consequences of I2-IR alkylation have not been reported previously. This study assessed by Western blot the effects of BU99006 on nischarin (candidate I1-IR), μ-OR (regulated by nischarin) and associated signalling mediators in the mouse brain. Acute treatment with BU99006 (20 mg/kg, i.p., 1-3 h) led to fast (peak at 1 h) and shortlasting (decline up to 3 h) upregulation of nischarin and μ-OR contents in the hippocampus (less or non-significant effects in cortex) and altered the expression of cytoskeletal β-actin (reduced contents at 3 h)...
March 23, 2017: Neurochemistry International
https://www.readbyqxmd.com/read/28339824/a-phase-i-trial-of-the-mek-inhibitor-selumetinib-azd6244-in-pediatric-patients-with-recurrent-or-refractory-low-grade-glioma-a-pediatric-brain-tumor-consortium-pbtc-study
#2
Anuradha Banerjee, Regina I Jakacki, Arzu Onar-Thomas, Shengjie Wu, Theodore Nicolaides, Tina Young Poussaint, Jason Fangusaro, Joanna Phillips, Arie Perry, David Turner, Michael Prados, Roger J Packer, Ibrahim Qaddoumi, Sridharan Gururangan, Ian F Pollack, Stewart Goldman, Lawrence A Doyle, Clinton F Stewart, James M Boyett, Larry E Kun, Maryam Fouladi
Background.: Activation of the mitogen-activated protein kinase pathway is important for growth of pediatric low-grade gliomas (LGGs). The aim of this study was to determine the recommended phase II dose (RP2D) and the dose-limiting toxicities (DLTs) of the MEK inhibitor selumetinib in children with progressive LGG. Methods.: Selumetinib was administered orally starting at 33 mg/m2/dose b.i.d., using the modified continual reassessment method. Pharmacokinetic analysis was performed during the first course...
February 28, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/28337120/antidyskinetic-effects-of-mek-inhibitor-are-associated-with-multiple-neurochemical-alterations-in-the-striatum-of-hemiparkinsonian-rats
#3
Guiqin Chen, Shuke Nie, Chao Han, Kai Ma, Yan Xu, Zhentao Zhang, Stella M Papa, Xuebing Cao
L-DOPA-induced dyskinesia (LID) represents one of the major problems of the long-term therapy of patients with Parkinson's disease (PD). Although, the pathophysiologic mechanisms underlying LID are not completely understood, activation of the extracellular signal regulated kinase (ERK) is recognized to play a key role. ERK is phosphorylated by mitogen-activated protein kinase kinase (MEK), and thus MEK inhibitor can prevent ERK activation. Here the effect of the MEK inhibitor PD98059 on LID and the associated molecular changes were examined...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28336232/tgf%C3%AE-1-induces-endometrial-cancer-cell-adhesion-and-migration-by-up-regulating-integrin-%C3%AE-v%C3%AE-3-via-smad-independent-mek-erk1-2-signaling
#4
Siyuan Xiong, Christian Klausen, Jung-Chien Cheng, Peter C K Leung
Endometrial cancer is the most common, and second most lethal, gynecological malignancy, and its rates of incidence and death are growing. This is likely attributable to increased numbers of high-risk type II endometrial cancers which account for ~30% of cases but ~75% of deaths due to their aggressive and metastatic behaviour. Histopathological and in vitro functional studies suggest that aberrant TGFβ1 signaling may contribute to endometrial cancer development and the acquisition of invasive/metastatic characteristics...
March 21, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28329662/the-preneoplastic-genome-transcriptomic-drivers-of-squamous-cell-carcinoma-development
#5
Kenneth Y Tsai
Cutaneous squamous cell carcinoma (cuSCC) comprises 15-20% of all skin cancers, accounting for over 700,000 cases in the U.S. annually. Most cuSCC arise in association with a distinct precancerous lesion, the actinic keratosis (AK). In order to identify potential targets for molecularly targeted chemoprevention, we performed integrated cross-species genomic analysis of cuSCC development through the preneoplastic AK stage using matched human samples and a solar UV- driven Hairless mouse model. We performed RNA-seq and microRNA-seq on samples from both patients undergoing Mohs surgery and the mouse model...
September 15, 2016: Dermatology Online Journal
https://www.readbyqxmd.com/read/28329154/brugada-syndrome-induced-by-braf-and-mek-inhibitors-in-a-melanoma-patient
#6
Charlée Nardin, Morgane Colas, Marc Badoz, Blandine Roche-Kubler, Nicolas Meneveau, Eve Puzenat, François Aubin
No abstract text is available yet for this article.
March 18, 2017: European Heart Journal
https://www.readbyqxmd.com/read/28325255/mucosal-melanoma-of-the-head-and-neck
#7
REVIEW
Paolo Antonio Ascierto, Remo Accorona, Gerardo Botti, Davide Farina, Piero Fossati, Gemma Gatta, Helen Gogas, Davide Lombardi, Roberto Maroldi, Piero Nicolai, Marco Ravanelli, Vito Vanella
Mucosal melanoma of the head and neck is a very rare and aggressive malignancy with a very poor prognosis. The nasal cavity, paranasal sinuses, and oral cavity are the most common locations. One-, 3- and 5-year survival rates between 2000 and 2007 were 63%, 30% and 20%, respectively. Cigarette smoking seems to be a risk factor even though the evidence for this is very low. Clinical signs and symptoms are usually nonspecific. While surgery is considered the mainstay of treatment for most mucosal melanomas of the head and neck region, radiotherapy has a role in local control of the disease after surgery...
April 2017: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/28323857/myocardial-ischemia-reperfusion-enhances-transcriptional-expression-of-endothelin-1-and-vasoconstrictor-etb-receptors-via-the-protein-kinase-mek-erk1-2-signaling-pathway-in-rat
#8
Gry Freja Skovsted, Lars Schack Kruse, Lukas Adrian Berchtold, Anne-Sofie Grell, Karin Warfvinge, Lars Edvinsson
BACKGROUND: Coronary artery remodelling and vasospasm is a complication of acute myocardial ischemia and reperfusion. The underlying mechanisms are complex, but the vasoconstrictor peptide endothelin-1 is suggested to have an important role. This study aimed to determine whether the expression of endothelin-1 and its receptors are regulated in the myocardium and in coronary arteries after experimental ischemia-reperfusion. Furthermore, we evaluated whether treatment with a specific MEK1/2 inhibitor, U0126, modified the expression and function of these proteins...
2017: PloS One
https://www.readbyqxmd.com/read/28323848/7%C3%AE-hydroxycholesterol-induces-monocyte-macrophage-cell-expression-of-interleukin-8-via-c5a-receptor
#9
Hyok-Rae Cho, Yonghae Son, Sun-Mi Kim, Bo-Young Kim, Seong-Kug Eo, Young Chul Park, Koanhoi Kim
We investigated effects of 7-oxygenated cholesterol derivatives present in atherosclerotic lesions, 7α-hydroxycholesterol (7αOHChol), 7β-hydroxycholesterol (7βOHChol), and 7-ketocholesterol (7K), on IL-8 expression. Transcript levels of IL-8 and secretion of its corresponding gene product by monocytes/macrophages were enhanced by treatment with 7αOHChol and, to a lesser extent, 7K, but not by 7βOHChol. The 7-oxygenated cholesterol derivatives, however, did not change transcription of the IL-8 gene in vascular smooth muscle cells...
2017: PloS One
https://www.readbyqxmd.com/read/28323504/pembrolizumab-use-for-the-treatment-of-advanced-melanoma
#10
Pol Specenier
Until recently, overall long term survival in patients with stage IV melanoma was lower than 10 %. However, the treatment of melanoma has evolved rapidly over the last few years, with the advent of inhibitors of BRAF and MEK and of immunotherapeutic agents including ipilimumab, nivolumab, and pembrolizumab. Areas covered: This is a comprehensive review of the literature on the role of pembrolizumab in melanoma. Pembrolizumab is a Programmed Death Receptor 1 (PD-1) directed monoclonal antibody which is approved by FDA and EMA for the treatment of patients with metastatic melanoma...
March 21, 2017: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/28323034/co-targeting-of-egfr-and-autophagy-signaling-is-an-emerging-treatment-strategy-in-metastatic-colorectal-cancer
#11
Evangelos Koustas, Michalis V Karamouzis, Chrysovalantou Mihailidou, Dimitrios Schizas, Athanasios G Papavassiliou
The epidermal growth factor receptor (EGFR) and its associated pathway is a critical key regulator of CRC development and progression. The monoclonal antibodies (MoAbs) cetuximab and panitumumab, directed against EGFR, represent a major step forward in the treatment of metastatic colorectal cancer (mCRC), in terms of progression-free survival and overall survival in several clinical trials. However, the activity of anti-EGFR MoAbs appears to be limited to a subset of patients with mCRC. Studies have highlighted that acquired-resistance to anti-EGFR MoAbs biochemically converge into Ras/Raf/Mek/Erk and PI3K/Akt/mTOR pathways...
March 18, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28322749/cannabinoid-receptor-1-contributes-to-sprouted-innervation-in-endometrial-ectopic-growth-through-mitogen-activated-protein-kinase-activation
#12
Hongxiu Han, Xizi Liang, Juan Wang, Qianqian Zhao, Mei Yang, Weifang Rong, Guohua Zhang
The endocannabinoid system regulates neurite outgrowth and neurogenesis during development of the central nervous system. Cannabinoid receptor 1 (CB1R) is expressed in neurons, including the somata and fibers, that innervate the endometrial ectopic cyst in rats. Here, we investigated the contribution of CB1R and its downstream signaling to the innervation of endometrial ectopic growth. We found that intrathecal injection of a CB1R agonist enhanced both the density of protein gene product (PGP) 9.5-immunoreactive sprouted nerve fibers and the protein level of PGP 9...
March 17, 2017: Brain Research
https://www.readbyqxmd.com/read/28322340/signalling-mechanisms-mediating-zn-2-induced-trpm2-channel-activation-and-cell-death-in-microglial-cells
#13
Sharifah Syed Mortadza, Joan A Sim, Martin Stacey, Lin-Hua Jiang
Excessive Zn(2+) causes brain damage via promoting ROS generation. Here we investigated the role of ROS-sensitive TRPM2 channel in H2O2/Zn(2+)-induced Ca(2+) signalling and cell death in microglial cells. H2O2/Zn(2+) induced concentration-dependent increases in cytosolic Ca(2+) concentration ([Ca(2+)]c), which was inhibited by PJ34, a PARP inhibitor, and abolished by TRPM2 knockout (TRPM2-KO). Pathological concentrations of H2O2/Zn(2+) induced substantial cell death that was inhibited by PJ34 and DPQ, PARP inhibitors, 2-APB, a TRPM2 channel inhibitor, and prevented by TRPM2-KO...
March 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28321769/n-propargyl-caffeamide-paca-ameliorates-dopaminergic-neuronal-loss-and-motor-dysfunctions-in-mptp-mouse-model-of-parkinson-s-disease-and-in-mpp-induced-neurons-via-promoting-the-conversion-of-prongf-to-ngf
#14
Dan Luo, Jia Zhao, Yuanyuan Cheng, Simon Ming-Yuen Lee, Jianhui Rong
Insufficient production of nerve growth factor (NGF) is implicated in Parkinson's disease (PD). We recently discovered that caffeic acid derivative N-propargyl caffeamide (PACA) not only potentiated NGF-induced neurite outgrowth but also attenuated 6-hydroxydopamine neurotoxicity in neuronal culture. The aim of the present study was to investigate whether PACA could increase NGF levels against 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) neurotoxicity in a mouse PD model. We induced parkinsonism in mice by intraperitoneal injection of MPTP for seven consecutive days...
March 21, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28320730/prediction-of-the-transporter-mediated-drug-drug-interaction-potential-of-dabrafenib-and-its-major-circulating-metabolites
#15
Harma Ellens, Marta Johnson, Sarah K Lawrence, Cory A Watson, Liangfu Chen, Lauren E Richards-Peterson
The BRAF inhibitor dabrafenib was recently approved for the treatment of certain BRAF V600 mutation-positive tumors, either alone or in combination therapy with the MEK inhibitor trametinib. This article presents the dabrafenib transporter-mediated drug-drug interaction risk assessment, which is currently an important part of drug development, regulatory submission and drug registration. Dabrafenib and its major circulating metabolites (hydroxy-, carboxy- and desmethyl-dabrafenib) were investigated as inhibitors of the clinically relevant transporters Pgp, BCRP, OATP1B1, OATP1B3, OCT2, OAT1 and OAT3...
March 20, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28315521/systematic-morphological-profiling-of-human-gene-and-allele-function-via-cell-painting
#16
Mohammad Hossein Rohban, Shantanu Singh, Xiaoyun Wu, Julia B Berthet, Mark-Anthony Bray, Yashaswi Shrestha, Xaralabos Varelas, Jesse S Boehm, Anne E Carpenter
We hypothesized that human genes and disease-associated alleles might be systematically functionally annotated using morphological profiling of cDNA constructs, via a microscopy-based Cell Painting assay. Indeed, 50% of the 220 tested genes yielded detectable morphological profiles, which grouped into biologically meaningful gene clusters consistent with known functional annotation (e.g., the RAS-RAF-MEK-ERK cascade). We used novel subpopulation-based visualization methods to interpret the morphological changes for specific clusters...
March 18, 2017: ELife
https://www.readbyqxmd.com/read/28314720/rechallenge-with-braf-and-mek-inhibitors-has-antitumor-activity
#17
(no author information available yet)
Resistance to BRAF plus MEK inhibitors may be reversible in patients with BRAF(V600)-mutant melanoma.
March 17, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28314256/hydrogen-peroxide-enhances-tgf%C3%AE-mediated-epithelial-to-mesenchymal-transition-in-human-mammary-epithelial-mcf-10a-cells
#18
Daisuke Iizuka, Megumi Sasatani, Mary Helen Barcellos-Hoff, Kenji Kamiya
AIM: This study investigated the effect of reactive oxygen species (ROS) on transforming growth factor (TGF)-β-mediated epithelial-to-mesenchymal transition (EMT) in order to clarify the influence of ROS and TGFβ on the induction of dysplasia and ultimately, tumorigenesis. MATERIALS AND METHODS: Confluent MCF-10A human mammary epithelial cells were treated with H2O2 for 1 h, then reseeded at low density in the presence of TGFβ and cultured until confluence. RESULTS: Hydrogen peroxide (H2O2, 250 μM) enhanced TGFβ-mediated EMT, as evidenced by increased expression of EMT-associated transcription factors, which was accompanied by increased nuclear localization of phosphorylated SMAD family member 2 (SMAD2) and up-regulation of the TGFβ signaling pathway components mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK)...
March 2017: Anticancer Research
https://www.readbyqxmd.com/read/28314119/a-combined-in-vitro-assay-for-evaluation-of-neurotrophic-activity-and-cytotoxicity
#19
Narayan D Chaurasiya, Surabhi Shukla, Babu L Tekwani
Neurotrophic assays are phenotypic methods to identify molecules that stimulate differentiation of neuronal cells. Bioactive small molecules with neurotrophic actions hold great promise as therapeutic agents for the treatment of neurodegenerative diseases and neuronal injuries by virtue of their ability to stimulate neuritic outgrowth. A combined in vitro method, which measures neurotrophic activity and cytotoxicity in a single assay, has been described. This assay, performed in 96-well microplates with PC12 and Neuroscreen-1 (NS-1; a subclone of PC12) cells, is a simple tool for identification of new neurotrophic agents...
March 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28314099/protein-corona-of-magnetic-hydroxyapatite-scaffold-improves-cell-proliferation-via-activation-of-mitogen-activated-protein-kinase-signaling-pathway
#20
Yue Zhu, Qi Yang, Minggang Yang, Xiaohui Zhan, Fang Lan, Jing He, Zhongwei Gu, Yao Wu
The beneficial effect of magnetic scaffolds on the improvement of cell proliferation has been well documented. Nevertheless, the underlying mechanisms about the magnetic scaffolds stimulating cell proliferation remain largely unknown. Once the scaffold enters into the biological fluids, a protein corona forms and directly influences the biological function of scaffold. This study aimed at investigating the formation of protein coronas on hydroxyapatite (HA) and magnetic hydroxyapatite (MHA) scaffolds in vitro and in vivo, and consequently its effect on regulating cell proliferation...
March 21, 2017: ACS Nano
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