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https://www.readbyqxmd.com/read/28822838/scavenging-reactive-oxygen-species-inhibits-status-epilepticus-induced-neuroinflammation
#1
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/28821646/location-of-the-mesopontine-neurons-responsible-for-maintanance-of-anesthetic-loss-of-consciousness
#2
Anne Minert, Shai-Lee Yatziv, Marshall Devor
The transition from wakefulness to general anesthesia is widely attributed to suppressive actions of anesthetic molecules distributed by the systemic circulation to the cerebral cortex (for amnesia and loss-of-consciousness) and to the spinal cord (for atonia and antinociception). An alternative hypothesis proposes that anesthetics act on one or more brainstem or diencephalic nuclei, with suppression of cortex and spinal cord mediated by dedicated axonal pathways. We previously documented induction of an anesthesia-like state in rats by microinjection of small amounts of GABAA-R agonists into an upper brainstem region named the mesopontine tegmental anesthesia area(MPTA)...
August 16, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28821610/a-screen-for-kinase-inhibitors-identifies-antimicrobial-imidazopyridine-aminofurazans-as-specific-inhibitors-of-the-listeria-monocytogenes-pasta-kinase-prka
#3
Adam J Schaenzer, Nathan Wlodarchak, David H Drewry, William J Zuercher, Warren E Rose, Rob Striker, John-Demian Sauer
Bacterial signaling systems such as protein kinases and quorum sensing have become increasingly attractive targets for the development of novel antimicrobial agents in a time of rising antibiotic resistance. The family of bacterial Penicillin-binding-protein And Serine/Threonine kinase-Associated (PASTA) kinases is of particular interest due to the role of these kinases in regulating resistance to β-lactam antibiotics. As such, small-molecule kinase inhibitors that target PASTA kinases may prove beneficial as treatments adjunctive to β-lactam therapy...
August 16, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28820976/a-hydrophobic-organelle-probe-based-on-aggregation-induced-emission-nanosuspension-preparation-and-direct-use-for-endoplasmic-reticulum-imaging-in-living-cells
#4
Sichao Zheng, Cuihong Huang, Xuyan Zhao, Yong Zhang, Shuwen Liu, Qiuhua Zhu
Organic fluorophores have a wide range of biological uses and are usually needed to be prepared as water-soluble compounds or nanoparticles for applications in aqueous biosystems owing to their hydrophobic properties, which often is a complex, time-consuming and high-cost process. Here, the nanoparticle preparation of hydrophobic fluorophores and their application in cell imaging have been investigated. It was found: a) fetal bovine serum (FBS) shows an excellent dispersion effect on hydrophobic small-molecule organic compounds; b) a hydrophobic C6-unsubstituted tetrahydropyrimidine (Me-THP-Naph) can be prepared as nanosuspensions utilizing cell culture medium with 10% FBS and directly be used as a specific real-time imaging probe for the endoplasmic reticulum (ER), a dynamic organelle playing a crucial role in many cellular processes...
August 8, 2017: Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy
https://www.readbyqxmd.com/read/28820965/systematic-identification-of-mcu-modulators-by-orthogonal-interspecies-chemical-screening
#5
Daniela M Arduino, Jennifer Wettmarshausen, Horia Vais, Paloma Navas-Navarro, Yiming Cheng, Anja Leimpek, Zhongming Ma, Alba Delrio-Lorenzo, Andrea Giordano, Cecilia Garcia-Perez, Guillaume Médard, Bernhard Kuster, Javier García-Sancho, Dejana Mokranjac, J Kevin Foskett, M Teresa Alonso, Fabiana Perocchi
The mitochondrial calcium uniporter complex is essential for calcium (Ca(2+)) uptake into mitochondria of all mammalian tissues, where it regulates bioenergetics, cell death, and Ca(2+) signal transduction. Despite its involvement in several human diseases, we currently lack pharmacological agents for targeting uniporter activity. Here we introduce a high-throughput assay that selects for human MCU-specific small-molecule modulators in primary drug screens. Using isolated yeast mitochondria, reconstituted with human MCU, its essential regulator EMRE, and aequorin, and exploiting a D-lactate- and mannitol/sucrose-based bioenergetic shunt that greatly minimizes false-positive hits, we identify mitoxantrone out of more than 600 clinically approved drugs as a direct selective inhibitor of human MCU...
August 17, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28820953/a-fluorescence-based-high-throughput-assay-for-the-identification-of-anticancer-reagents-targeting-fructose-1-6-bisphosphate-aldolase
#6
Eun Jeong Cho, Ashwini K Devkota, Gabriel Stancu, Ramakrishna Edupunganti, Garth Powis, Kevin N Dalby
A high rate of glycolysis, which supplies energy and materials for anabolism, is observed in a wide range of tumor cells, making it a potential pathway to control cancer growth. ALDOA is a multifunctional enzyme in the glycolytic pathway and also promotes HIF-1α, which is of importance in hypoxic solid tumors. The current method for assaying ALDOA activity involves monitoring the consumption of NADH in vitro using absorbance or intrinsic fluorescence via a coupled enzymatic reaction. Here, we report the development of a homogeneous biochemical assay that can overcome limitations of current methods, in particular for the application of high-throughput drug screening...
August 1, 2017: SLAS Discovery
https://www.readbyqxmd.com/read/28820390/small-molecule-inhibitors-of-dna-pk-for-tumor-sensitization-to-anticancer-therapy
#7
M Pospisilova, M Seifrtova, M Rezacova
The most sensitive cell structure - a DNA molecule, is the common target of cancer therapy. DNA damage response (controlled by enzymes from the phosphatidylinositol 3-kinase-related kinases family - PIKK) presents many encouraging targets for improving both conventional cytotoxic anticancer therapy and individualized monotherapy. DNA-dependent protein kinase (DNA-PK) is a member of the PIKK superfamily and plays an important role in the detection and repair of DNA double-strand breaks via the non-homologous end-joining pathway...
June 2017: Journal of Physiology and Pharmacology: An Official Journal of the Polish Physiological Society
https://www.readbyqxmd.com/read/28820254/blockade-of-asparagine-endopeptidase-inhibits-cancer-metastasis
#8
Qi Qi, Obiamaka Obianyo, Yuhong Du, Haian Fu, Shiyong Li, Keqiang Ye
Asparagine endopeptidase (AEP), also called legumain, is highly expressed in various solid tumors, promoting cancer cell invasion, migration, and metastasis. It has been proposed to be a prognostic marker and therapeutic target for cancer treatment. However, an effective nonpeptide, small-molecule inhibitor against this protease has not yet been identified. Here we show that a family of xanthine derivatives selectively inhibit AEP and suppress matrix metalloproteinase (MMP) cleavage, leading to the inhibition of cancer metastasis...
August 18, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28819166/histone-protein-deacetylase-11-targeting-promotes-foxp3-treg-function
#9
Jianbing Huang, Liqing Wang, Satinder Dahiya, Ulf H Beier, Rongxiang Han, Arabinda Samanta, Joel Bergman, Eduardo M Sotomayor, Edward Seto, Alan P Kozikowski, Wayne W Hancock
Current interest in Foxp3+ T-regulatory (Treg) cells as therapeutic targets in transplantation is largely focused on their harvesting pre-transplant, expansion and infusion post-transplantation. An alternate strategy of pharmacologic modulation of Treg function using histone/protein deacetylase inhibitors (HDACi) may allow more titratable and longer-term dosing. However, the effects of broadly acting HDACi vary, such that HDAC isoform-selective targeting is likely required. We report data from mice with constitutive or conditional deletion of HDAC11 within Foxp3+ Treg cells, and their use, along with small molecule HDAC11 inhibitors, in allograft models...
August 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28819026/therapeutic-targeting-of-the-cbp-p300-bromodomain-blocks%C3%A2-the-growth-of-castration-resistant-prostate-cancer
#10
Lingyan Jin, Jesse Garcia, Emily Chan, Cecile de la Cruz, Ehud Segal, Mark Merchant, Samir Kharbanda, Ryan Raisner, Peter M Haverty, Zora Modrusan, Justin Ly, Edna Choo, Susan Kaufman, Maureen H Beresini, F Anthony Romero, Steven Magnuson, Karen E Gascoigne
Resistance invariably develops to anti-androgen therapies used to treat newly diagnosed prostate cancers, but effective treatments for castration-resistant disease remain elusive. Here we report that the transcriptional co-activator CBP/p300 is required to maintain the growth of castration-resistant prostate cancer. To exploit this vulnerability, we developed a novel small-molecule inhibitor of the CBP/p300 bromodomain that blocks prostate cancer growth in vitro and in vivo. Molecular dissection of the consequences of drug treatment revealed a critical role for CBP/p300 in histone acetylation required for the transcriptional activity of the androgen receptor and its target gene expression...
August 17, 2017: Cancer Research
https://www.readbyqxmd.com/read/28818724/enzyme-sensitive-smart-inulin-dehydropeptide-conjugate-self-assembles-into-nanostructures-useful-for-targeted-delivery-of-ornidazole
#11
Kriti Shivhare, Charu Garg, Ayushi Priyam, Alka Gupta, Ashwani Kumar Sharma, Pradeep Kumar
Molecular self-assembly of biodegradable amphiphilic polymers allows rational design of biocompatible nanomaterials for drug delivery. Use of substituted polysaccharides for such applications offers the ease of design and synthesis, and provides higher biofunctionality and biocompatibility to nanomaterials. The present work focuses on the synthesis, characterization and potential biomedical applications of self-assembled polysaccharide-based materials. We demonstrated that the synthesized amphiphilic inulin self-assembled in aqueous medium into nanostructures with average size in the range of 146-486nm and encapsulated hydrophobic therapeutic molecule, ornidazole...
August 14, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28818206/pharmacological-and-activated-fibroblast%C3%A2-targeting-of-g%C3%AE-%C3%AE-grk2-after%C3%A2-myocardial-ischemia-attenuates-heart-failure-progression
#12
Joshua G Travers, Fadia A Kamal, Iñigo Valiente-Alandi, Michelle L Nieman, Michelle A Sargent, John N Lorenz, Jeffery D Molkentin, Burns C Blaxall
BACKGROUND: Cardiac fibroblasts are a critical cell population responsible for myocardial extracellular matrix homeostasis. Upon injury or pathological stimulation, these cells transform to an activated myofibroblast state and play a fundamental role in myocardial fibrosis and remodeling. Chronic sympathetic overstimulation, a hallmark of heart failure (HF), induces pathological signaling through G protein βγ (Gβγ) subunits and their interaction with G protein-coupled receptor kinase 2 (GRK2)...
August 22, 2017: Journal of the American College of Cardiology
https://www.readbyqxmd.com/read/28818073/role-of-the-lncrna-abhd11-as1-in-the-tumorigenesis-and-progression-of-epithelial-ovarian-cancer-through-targeted-regulation-of-rhoc
#13
Dan-Dan Wu, Xi Chen, Kai-Xuan Sun, Li-Li Wang, Shuo Chen, Yang Zhao
BACKGROUND: There is increasing evidence in support of the role of lncRNAs in tumor cell proliferation, differentiation and apoptosis. METHODS: We examined the expression of the lncRNA ABHD11-AS1 in epithelial ovarian cancer (EOC) tissues and normal ovarian tissues by real-time quantitative PCR (qRT-PCR). After inducing ABHD11-AS1 downregulation by small interfering RNA (siRNA) or ABHD11-AS1 overexpression by plasmid transfection, we examined the EOC cell phenotypes and expression of related molecules...
August 17, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28817181/introduction-of-hsa-mir-103a-and-hsa-mir-1827-and-hsa-mir-137-as-new-regulators-of-wnt-signaling-pathway-and-their-relation-to-colorectal-carcinoma
#14
Ali Fasihi, Bahram M Soltani, Amir Atashi, Shirzad Nasiri
Wnt signaling is hyper-activated in most of human cancers including colorectal carcinoma (CRC). Therefore, the introduction of new regulators for Wnt pathway possesses promising diagnostic and therapeutic applications in cancer medicine. Bioinformatics analysis introduced hsa-miR-103a, hsa-miR-1827, and hsa-miR-137 as potential regulators of Wnt signaling pathway. Here, we intended to examine the effect of these human miRNAs on Wnt signaling pathway components, on the cell cycle progression in CRC originated cell lines and their expression in CRC tissues...
August 17, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28817175/drug-development-for-breast-colorectal-and-non-small-cell-lung-cancers-from-1979-to-2014
#15
Nancy A Nixon, Omar F Khan, Hasiba Imam, Patricia A Tang, Jose Monzon, Haocheng Li, Gavin Sun, Doreen Ezeife, Sunil Parimi, Scot Dowden, Vincent C Tam
BACKGROUND: Understanding the drug development pathway is critical for streamlining the development of effective cancer treatments. The objective of the current study was to delineate the drug development timeline and attrition rate of different drug classes for common cancer disease sites. METHODS: Drugs entering clinical trials for breast, colorectal, and non-small cell lung cancer were identified using a pharmaceutical business intelligence database. Data regarding drug characteristics, clinical trials, and approval dates were obtained from the database, clinical trial registries, PubMed, and regulatory Web sites...
August 17, 2017: Cancer
https://www.readbyqxmd.com/read/28815832/targeting-the-genome-stability-hub-ctf4-by-stapled-peptide-design
#16
Yuteng Wu, Fabrizio Villa, Joseph Maman, Lina Dobnikar, Yu H Lau, Aline C Simon, Karim Labib, David R Spring, Luca Pellegrini
Exploitation of synthetic lethality by small-molecule targeting of pathways that maintain genomic stability is an attractive chemotherapeutic approach. The Ctf4/AND-1 protein hub that links DNA replication, repair and chromosome segregation, represents a novel target for the synthetic lethality approach. Here we report the design, optimization, and validation of double-click stapled peptides encoding the Ctf4-interacting peptide (CIP) of the replicative helicase subunit Sld5. Screening stapling positions in the Sld5 CIP, we identified an unorthodox i,i+6 stapled peptide with improved, sub-micromolar binding to Ctf4...
August 17, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28815537/from-heterochromatin-to-long-noncoding-rnas-in-drosophila-expanding-the-arena-of-gene-function-and-regulation
#17
Subhash C Lakhotia
Recent years have witnessed a remarkable interest in exploring the significance of pervasive noncoding transcripts in diverse eukaryotes. Classical cytogenetic studies using the Drosophila model system unraveled the perplexing attributes and "functions" of the "gene"-poor heterochromatin. Recent molecular studies in the fly model are likewise revealing the very diverse and significant roles played by long noncoding RNAs (lncRNAs) in development, gene regulation, chromatin organization, cell and nuclear architecture, etc...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28812378/bevacizumab-in-advanced-lung-cancer-state-of-the-art
#18
Sandra Assoun, Solenn Brosseau, Christelle Steinmetz, Valérie Gounant, Gérard Zalcman
Despite recent advances in metastatic lung cancer treatment with the advent of immune checkpoint inhibitors and molecules targeting addictive genomic abnormalities, prognosis of most of the patients remains unfavorable. Combination approaches with older drugs, such as bevacizumab, should be thus envisioned. Bevacizumab is a monoclonal anti-VEGF antibody, approved by the US FDA and the EMA in first-line and maintenance settings of advanced nonsquamous non-small-cell lung cancer (NSCLC) treatment, in association with platinum-based chemotherapy...
August 16, 2017: Future Oncology
https://www.readbyqxmd.com/read/28811361/chemoradiotherapy-resistance-in-colorectal-cancer-cells-is-mediated-by-wnt-%C3%AE-catenin-signaling
#19
Georg Emons, Melanie Spitzner, Sebastian Reineke, Janneke Möller, Noam Auslander, Frank Kramer, Yue Hu, Tim Beissbarth, Hendrik A Wolff, Margret Rave-Fränk, Elisabeth Heßmann, Jochen Gaedcke, B Michael Ghadimi, Steven Johnsen, Thomas Ried, Marian Grade
Activation of Wnt/β-catenin signaling plays a central role in the development and progression of colorectal cancer (CRC). The Wnt-transcription factor, TCF7L2, is overexpressed in primary rectal cancers that are resistant to chemoradiotherapy (CRT) and TCF7L2 mediates resistance to CRT. However, it is unclear whether the resistance is mediated by a TCF7L2 inherent mechanism or Wnt/β-catenin signaling in general. Here, inhibition of β-catenin by siRNAs or a small molecule inhibitor (XAV-939) resulted in sensitization of CRC cells to CRT...
August 15, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28810250/cerebral-small-vessel-disease-is-associated-with-dysregulation-in-the-ubiquitin-proteasome-system-and-other-major-cellular-pathways-in-specific-brain-regions
#20
Marie-Françoise Ritz, Caspar Grond-Ginsbach, Felix Fluri, Manja Kloss, Markus Tolnay, Nils Peters, Stefan Engelter, Philippe Lyrer
BACKGROUND/AIMS: Cerebral small vessel disease (SVD) is characterized by periventricular white matter (WM) changes and can lead to vascular dementia, the second most common form of age-dependent dementia. The pathogenesis of the disease remains poorly understood, and studies of its molecular basis are limited. By profiling gene expression of dissected postmortem brain tissue in SVD patients and comparisons with tissue of nonneurological controls, we aimed to identify genes and processes that are involved in the pathogenesis of SVD to gain new pathogenetic insights...
August 16, 2017: Neuro-degenerative Diseases
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