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Author (up) Akhurst, R.J.; Hata, A. file  url
openurl 
  Title Targeting the TGFbeta signalling pathway in disease Type Journal Article
  Year 2012 Publication Nature Reviews. Drug Discovery Abbreviated Journal Nat Rev Drug Discov  
  Volume 11 Issue 10 Pages 790-811  
  Keywords Animals; Drug Delivery Systems/*methods; Humans; Protein Binding/physiology; Receptors, Transforming Growth Factor beta/antagonists & inhibitors/metabolism; Signal Transduction/drug effects/*physiology; Transforming Growth Factor beta/*antagonists & inhibitors/*physiology  
  Abstract Many drugs that target transforming growth factor-beta (TGFbeta) signalling have been developed, some of which have reached Phase III clinical trials for a number of disease applications. Preclinical and clinical studies indicate the utility of these agents in fibrosis and oncology, particularly in augmentation of existing cancer therapies, such as radiation and chemotherapy, as well as in tumour vaccines. There are also reports of specialized applications, such as the reduction of vascular symptoms of Marfan syndrome. Here, we consider why the TGFbeta signalling pathway is a drug target, the potential clinical applications of TGFbeta inhibition, the issues arising with anti-TGFbeta therapy and how these might be tackled using personalized approaches to dosing, monitoring of biomarkers as well as brief and/or localized drug-dosing regimens.  
  Call Number Serial 1548  
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Author (up) Atherton, P.J.; Babraj, J.; Smith, K.; Singh, J.; Rennie, M.J.; Wackerhage, H. file  url
openurl 
  Title Selective activation of AMPK-PGC-1alpha or PKB-TSC2-mTOR signaling can explain specific adaptive responses to endurance or resistance training-like electrical muscle stimulation Type Journal Article
  Year 2005 Publication FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology Abbreviated Journal Faseb J  
  Volume 19 Issue 7 Pages 786-788  
  Keywords Adaptation, Physiological; Adenylate Kinase/*metabolism; Animals; Electric Stimulation; Enzyme Activation; Male; Mitogen-Activated Protein Kinases/metabolism; Muscle Contraction; Muscle Proteins/biosynthesis; Muscle, Skeletal/*physiology; Myofibrils/metabolism; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phosphorylation; Physical Conditioning, Animal; Physical Endurance/physiology; Physical Exertion; Protein Kinases/*metabolism; Proto-Oncogene Proteins c-akt/*metabolism; RNA-Binding Proteins/*metabolism; Rats; Rats, Wistar; Sarcoplasmic Reticulum/metabolism; Signal Transduction; TOR Serine-Threonine Kinases; Transcription Factors/*metabolism; Tumor Suppressor Proteins/*metabolism  
  Abstract Endurance training induces a partial fast-to-slow muscle phenotype transformation and mitochondrial biogenesis but no growth. In contrast, resistance training mainly stimulates muscle protein synthesis resulting in hypertrophy. The aim of this study was to identify signaling events that may mediate the specific adaptations to these types of exercise. Isolated rat muscles were electrically stimulated with either high frequency (HFS; 6x10 repetitions of 3 s-bursts at 100 Hz to mimic resistance training) or low frequency (LFS; 3 h at 10 Hz to mimic endurance training). HFS significantly increased myofibrillar and sarcoplasmic protein synthesis 3 h after stimulation 5.3- and 2.7-fold, respectively. LFS had no significant effect on protein synthesis 3 h after stimulation but increased UCP3 mRNA 11.7-fold, whereas HFS had no significant effect on UCP3 mRNA. Only LFS increased AMPK phosphorylation significantly at Thr172 by approximately 2-fold and increased PGC-1alpha protein to 1.3 times of control. LFS had no effect on PKB phosphorylation but reduced TSC2 phosphorylation at Thr1462 and deactivated translational regulators. In contrast, HFS acutely increased phosphorylation of PKB at Ser473 5.3-fold and the phosphorylation of TSC2, mTOR, GSK-3beta at PKB-sensitive sites. HFS also caused a prolonged activation of the translational regulators p70 S6k, 4E-BP1, eIF-2B, and eEF2. These data suggest that a specific signaling response to LFS is a specific activation of the AMPK-PGC-1alpha signaling pathway which may explain some endurance training adaptations. HFS selectively activates the PKB-TSC2-mTOR cascade causing a prolonged activation of translational regulators, which is consistent with increased protein synthesis and muscle growth. We term this behavior the “AMPK-PKB switch.” We hypothesize that the AMPK-PKB switch is a mechanism that partially mediates specific adaptations to endurance and resistance training, respectively.  
  Call Number Serial 2075  
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Author (up) Blair, J.M.A.; Webber, M.A.; Baylay, A.J.; Ogbolu, D.O.; Piddock, L.J.V. file  url
doi  openurl
  Title Molecular mechanisms of antibiotic resistance Type Journal Article
  Year 2015 Publication Nature Reviews. Microbiology Abbreviated Journal Nat Rev Microbiol  
  Volume 13 Issue 1 Pages 42-51  
  Keywords *Anti-Bacterial Agents/metabolism/pharmacology; *Bacteria/drug effects/metabolism/pathogenicity; *Drug Resistance, Bacterial; Signal Transduction  
  Abstract Antibiotic-resistant bacteria that are difficult or impossible to treat are becoming increasingly common and are causing a global health crisis. Antibiotic resistance is encoded by several genes, many of which can transfer between bacteria. New resistance mechanisms are constantly being described, and new genes and vectors of transmission are identified on a regular basis. This article reviews recent advances in our understanding of the mechanisms by which bacteria are either intrinsically resistant or acquire resistance to antibiotics, including the prevention of access to drug targets, changes in the structure and protection of antibiotic targets and the direct modification or inactivation of antibiotics.  
  Call Number Serial 1136  
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Author (up) Bonello, T.T.; Stehn, J.R.; Gunning, P.W. file  url
openurl 
  Title New approaches to targeting the actin cytoskeleton for chemotherapy Type Journal Article
  Year 2009 Publication Future Medicinal Chemistry Abbreviated Journal Future Med Chem  
  Volume 1 Issue 7 Pages 1311-1331  
  Keywords Actin Cytoskeleton/chemistry/*drug effects/physiology; Actin-Related Protein 2-3 Complex/genetics/metabolism; Cortactin/genetics/metabolism; Destrin/genetics/metabolism; Gelsolin/genetics/metabolism; Humans; Microfilament Proteins/*antagonists & inhibitors/chemistry; Myosin Type II/genetics/metabolism; Neoplasms/drug therapy/metabolism; Signal Transduction; Tropomyosin/genetics/metabolism; Wiskott-Aldrich Syndrome Protein Family/genetics/metabolism  
  Abstract The actin cytoskeleton is indispensable for normal cellular function. In particular, several actin-based structures coordinate cellular motility, a process hijacked by tumor cells in order to facilitate their propagation to distant sites. The actin cytoskeleton, therefore, represents a point for chemotherapeutic intervention. The challenge in disrupting the actin cytoskeleton is in preserving actin-driven contraction of cardiac and skeletal muscle. By targeting actin-binding proteins with altered expression in malignancy, it may be possible to achieve tumor-specific toxicity. A number of actin-binding proteins act cooperatively and synergistically to regulate actin structures required for motility. The actin cytoskeleton is characterized by a significant degree of plasticity. Targeting specific actin-binding proteins for chemotherapy will only be successful if no other compensatory mechanisms exist.  
  Call Number Serial 1054  
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Author (up) Bonello, T.T.; Stehn, J.R.; Gunning, P.W. file  url
doi  openurl
  Title New approaches to targeting the actin cytoskeleton for chemotherapy Type Journal Article
  Year 2009 Publication Future Medicinal Chemistry Abbreviated Journal Future Med Chem  
  Volume 1 Issue 7 Pages 1311-1331  
  Keywords Actin Cytoskeleton/chemistry/*drug effects/physiology; Actin-Related Protein 2-3 Complex/genetics/metabolism; Cortactin/genetics/metabolism; Destrin/genetics/metabolism; Gelsolin/genetics/metabolism; Humans; Microfilament Proteins/*antagonists & inhibitors/chemistry; Myosin Type II/genetics/metabolism; Neoplasms/drug therapy/metabolism; Signal Transduction; Tropomyosin/genetics/metabolism; Wiskott-Aldrich Syndrome Protein Family/genetics/metabolism  
  Abstract The actin cytoskeleton is indispensable for normal cellular function. In particular, several actin-based structures coordinate cellular motility, a process hijacked by tumor cells in order to facilitate their propagation to distant sites. The actin cytoskeleton, therefore, represents a point for chemotherapeutic intervention. The challenge in disrupting the actin cytoskeleton is in preserving actin-driven contraction of cardiac and skeletal muscle. By targeting actin-binding proteins with altered expression in malignancy, it may be possible to achieve tumor-specific toxicity. A number of actin-binding proteins act cooperatively and synergistically to regulate actin structures required for motility. The actin cytoskeleton is characterized by a significant degree of plasticity. Targeting specific actin-binding proteins for chemotherapy will only be successful if no other compensatory mechanisms exist.  
  Call Number Serial 1081  
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Author (up) Borre, Y.E.; Moloney, R.D.; Clarke, G.; Dinan, T.G.; Cryan, J.F. file  url
openurl 
  Title The impact of microbiota on brain and behavior: mechanisms & therapeutic potential Type Journal Article
  Year 2014 Publication Advances in Experimental Medicine and Biology Abbreviated Journal Adv Exp Med Biol  
  Volume 817 Issue Pages 373-403  
  Keywords Animals; Anti-Bacterial Agents/pharmacology; *Behavior; Brain/*physiology; Brain Diseases/therapy; Cognition; Humans; Intestines/microbiology; Microbiome; Microbiota/*physiology; Probiotics/pharmacology; Signal Transduction; Tryptophan/metabolism  
  Abstract There is increasing evidence that host-microbe interactions play a key role in maintaining homeostasis. Alterations in gut microbial composition is associated with marked changes in behaviors relevant to mood, pain and cognition, establishing the critical importance of the bi-directional pathway of communication between the microbiota and the brain in health and disease. Dysfunction of the microbiome-brain-gut axis has been implicated in stress-related disorders such as depression, anxiety and irritable bowel syndrome and neurodevelopmental disorders such as autism. Bacterial colonization of the gut is central to postnatal development and maturation of key systems that have the capacity to influence central nervous system (CNS) programming and signaling, including the immune and endocrine systems. Moreover, there is now expanding evidence for the view that enteric microbiota plays a role in early programming and later response to acute and chronic stress. This view is supported by studies in germ-free mice and in animals exposed to pathogenic bacterial infections, probiotic agents or antibiotics. Although communication between gut microbiota and the CNS are not fully elucidated, neural, hormonal, immune and metabolic pathways have been suggested. Thus, the concept of a microbiome-brain-gut axis is emerging, suggesting microbiota-modulating strategies may be a tractable therapeutic approach for developing novel treatments for CNS disorders.  
  Call Number Serial 2003  
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Author (up) Bucher, D.; Buchner, E. file  url
openurl 
  Title Stimulating PACalpha increases miniature excitatory junction potential frequency at the Drosophila neuromuscular junction Type Journal Article
  Year 2009 Publication Journal of Neurogenetics Abbreviated Journal J Neurogenet  
  Volume 23 Issue 1-2 Pages 220-224  
  Keywords Adenylyl Cyclases/*physiology; Animals; Cyclic AMP/physiology; Drosophila/*physiology; Enzyme Activation/radiation effects; Excitatory Postsynaptic Potentials/physiology; Light Signal Transduction/physiology; Miniature Postsynaptic Potentials/physiology; Motor Neurons/enzymology; Neuromuscular Junction/*physiology; Photic Stimulation/methods; Synapses/enzymology/physiology  
  Abstract Photoactivated adenylate cyclase alpha (PACalpha) is a light-activated adenylate cyclase that was originally cloned from the eye spot of the protozoan Euglena gracilis. PACalpha has been shown to rapidly increase intracellular cyclic adenosine monophosphate (cAMP) in vivo in Xenopus oocytes and HEK293 cells, increase the spike width in Aplysia sensory neurons, and modify behavior in Drosophila. Using the GAL4 UAS system, we heterologously expressed PACalpha in motorneurons and quantified the effects of its activation at the neuromuscular junction of the Drosophila third instar wandering larva, a well-characterized model synapse. By recording from body-wall muscle 6, we show that the presynaptic activation of PACalpha with blue light significantly increased miniature excitatory junction potential (mEJP) frequency in the presence of calcium with a delay of about 1 minute. Similar effects have been observed in previous studies that utilized adenylate cyclase agonists (Forskolin) or membrane-permeable cAMP analogs [dibutyryl cAMP and 4-chlorophenylthio-(CPT)-cAMP] to increase presynaptic cAMP concentrations. PACalpha's efficacy in combination with its specificity make it an invaluable tool for the rapid regulation of cAMP in vivo and for investigating the mechanisms by which cAMP can modulate synaptic transmission and neuronal plasticity in Drosophila.  
  Call Number Serial 1255  
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Author (up) Burgos-Ramos, E.; Chowen, J.A.; Argente, J.; Barrios, V. file  url
openurl 
  Title Regional and temporal differences in leptin signaling in rat brain Type Journal Article
  Year 2010 Publication General and Comparative Endocrinology Abbreviated Journal Gen Comp Endocrinol  
  Volume 167 Issue 1 Pages 143-152  
  Keywords Animals; Blotting, Western; Brain/*metabolism; Cerebellum/metabolism; Hippocampus/metabolism; Hypothalamus/metabolism; Leptin/*metabolism; Male; Radioimmunoprecipitation Assay; Rats; Rats, Wistar; Signal Transduction/*physiology; Time Factors  
  Abstract Leptin regulates energy homeostasis through activation of different hypothalamic pathways. Evidence indicates that leptin is a pleiotropic hormone that acts on many brain areas, altering food intake, metabolism, and locomotion, among other functions. Because short-term effects of leptin infusion and intracellular pathways in other brain areas involved in food regulation have not been thoroughly analysed, we have studied the acute effect of intracerebroventricular leptin administration on the levels of the long form of leptin receptor (Ob-Rb), as well as on activation of Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3), protein kinase B (Akt), extracellular regulated kinases (ERKs) and levels of suppressor of cytokine signaling-3 (SOCS3) in the hypothalamus, hippocampus, frontal cortex and cerebellum of adult male Wistar rats at 15min, 1 and 6h. The levels of Ob-Rb increased at 6h in hypothalamus only. Leptin activated the JAK2/STAT3 pathway in all areas, although in a temporally specific pattern. In contrast, this hormone decreased Akt activation in hypothalamus, hippocampus and cerebellum and ERK activation in frontal cortex, while it increased ERK activation in hypothalamus and hippocampus. These differences in modulation of Ob-Rb levels and signaling indicate that the rapid effects of leptin in non-hypothalamic areas are mediated, at least in part, through the intracellular pathways involved in hypothalamic energy balance, but in a temporally specific manner.  
  Call Number Serial 218  
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Author (up) Caunt, C.J.; Sale, M.J.; Smith, P.D.; Cook, S.J. file  url
openurl 
  Title MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road Type Journal Article
  Year 2015 Publication Nature Reviews. Cancer Abbreviated Journal Nat Rev Cancer  
  Volume 15 Issue 10 Pages 577-592  
  Keywords Humans; MAP Kinase Kinase 1/*antagonists & inhibitors/metabolism; MAP Kinase Kinase 2/*antagonists & inhibitors/metabolism; MAP Kinase Signaling System/physiology; Neoplasms/*drug therapy/metabolism; Protein Kinase Inhibitors/*therapeutic use; Signal Transduction/drug effects  
  Abstract The role of the ERK signalling pathway in cancer is thought to be most prominent in tumours in which mutations in the receptor tyrosine kinases RAS, BRAF, CRAF, MEK1 or MEK2 drive growth factor-independent ERK1 and ERK2 activation and thence inappropriate cell proliferation and survival. New drugs that inhibit RAF or MEK1 and MEK2 have recently been approved or are currently undergoing late-stage clinical evaluation. In this Review, we consider the ERK pathway, focusing particularly on the role of MEK1 and MEK2, the 'gatekeepers' of ERK1/2 activity. We discuss their validation as drug targets, the merits of targeting MEK1 and MEK2 versus BRAF and the mechanisms of action of different inhibitors of MEK1 and MEK2. We also consider how some of the systems-level properties (intrapathway regulatory loops and wider signalling network connections) of the ERK pathway present a challenge for the success of MEK1 and MEK2 inhibitors, discuss mechanisms of resistance to these inhibitors, and review their clinical progress.  
  Call Number Serial 2024  
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Author (up) Cleary, M.D.; Meiering, C.D.; Jan, E.; Guymon, R.; Boothroyd, J.C. file  url
openurl 
  Title Biosynthetic labeling of RNA with uracil phosphoribosyltransferase allows cell-specific microarray analysis of mRNA synthesis and decay Type Journal Article
  Year 2005 Publication Nature Biotechnology Abbreviated Journal Nat Biotechnol  
  Volume 23 Issue 2 Pages 232-237  
  Keywords Animals; Gene Expression Profiling/*methods; Gene Expression Regulation/*physiology; Humans; Metabolic Clearance Rate; Oligonucleotide Array Sequence Analysis/*methods; Pentosyltransferases/chemistry/*metabolism; RNA, Messenger/chemistry/*genetics/*metabolism; Signal Transduction/physiology; Staining and Labeling/methods; Toxoplasma/genetics/metabolism; Transcription Factors/*metabolism; Transcriptional Activation/*physiology  
  Abstract Standard microarrays measure mRNA abundance, not mRNA synthesis, and therefore cannot identify the mechanisms that regulate gene expression. We have developed a method to overcome this limitation by using the salvage enzyme uracil phosphoribosyltransferase (UPRT) from the protozoan Toxoplasma gondii. T. gondii UPRT has been well characterized because of its application in monitoring parasite growth: mammals lack this enzyme activity and thus only the parasite incorporates (3)H-uracil into its nucleic acids. In this study we used RNA labeling by UPRT to determine the roles of mRNA synthesis and decay in the control of gene expression during T. gondii asexual development. We also used this approach to specifically label parasite RNA during a mouse infection and to incorporate thio-substituted uridines into the RNA of human cells engineered to express T. gondii UPRT, indicating that engineered UPRT expression will allow cell-specific analysis of gene expression in organisms other than T. gondii.  
  Call Number Serial 1344  
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