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Pharmaceuticals, Volume 4, Issue 3 (March 2011) – 8 articles , Pages 429-566

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501 KiB  
Article
Carvedilol Attenuates Inflammatory-Mediated Cardiotoxicity in Daunorubicin-Induced Rats
by Flori R. Sari, Wawaimuli Arozal, Kenichi Watanabe, Meilei Harima, Punniyakoti T. Veeravedu, Rajarajan A. Thandavarayan, Kenji Suzuki, Somasundaram Arumugam, Vivian Soetikno and Makoto Kodama
Pharmaceuticals 2011, 4(3), 551-566; https://0-doi-org.brum.beds.ac.uk/10.3390/ph4030551 - 17 Mar 2011
Cited by 12 | Viewed by 8927
Abstract
Cardiotoxicity, which results from intense cardiac oxidative stress and inflammation, is the main limiting factor of the anthracyclines. Carvedilol, a beta blocker that is used as a multifunctional neurohormonal antagonist, has been shown to act not only as an anti-oxidant, but also as [...] Read more.
Cardiotoxicity, which results from intense cardiac oxidative stress and inflammation, is the main limiting factor of the anthracyclines. Carvedilol, a beta blocker that is used as a multifunctional neurohormonal antagonist, has been shown to act not only as an anti-oxidant, but also as an anti-inflammatory drug. This study was designed to evaluate whether carvedilol exerts a protective role against inflammation-mediated cardiotoxicity in the daunorubicin (DNR)-induced rats. Carvedilol was administered orally to the rats every day for 6 weeks at a cumulative dose of 9 mg/kg body weight DNR. DNR significantly induced cardiac damage and worsened cardiac function as well as increased cardiac mast cell density, elevating the myocardial protein and mRNA expression levels of tumor necrosis factor-α, vascular cell adhesion molecule-1, inter-cellular adhesion molecule-1, nuclear factor kappa-B, cyclooxygenase-2, monocyte chemotactic protein -1 and interleukin -6 compared to that in the control group. Cotreatment with carvedilol significantly attenuated the myocardial protein and mRNA expression levels of these inflammatory markers, decreased cardiac mast cell density, improved histological cardiac damage and cardiac functions. In conclusion, inflammation plays a significant role in DNR-induced cardiotoxicity, and carvedilol contributes to cardioprotection against inflammation-mediated cardiotoxicity in DNR-induced rats through its anti-inflammatory mechanism. Full article
(This article belongs to the Special Issue Betablockers)
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707 KiB  
Review
Soft X-ray Laser Microscopy of Lipid Rafts towards GPCR-Based Drug Discovery Using Time-Resolved FRET Spectroscopy
by Motoyoshi Baba, Tohru Kozasa, Takao Hamakubo, Hiroto Kuroda, Kazuyuki Masuda, Shin Yoneya and Tatsuhiko Kodama
Pharmaceuticals 2011, 4(3), 524-550; https://0-doi-org.brum.beds.ac.uk/10.3390/ph4030524 - 14 Mar 2011
Viewed by 8403
Abstract
Many signaling molecules involved in G protein-mediated signal transduction, which are present in the lipid rafts and believed to be controlled spatially and temporally, influence the potency and efficacy of neurotransmitter receptors and transporters. This has focus interest on lipid rafts and the [...] Read more.
Many signaling molecules involved in G protein-mediated signal transduction, which are present in the lipid rafts and believed to be controlled spatially and temporally, influence the potency and efficacy of neurotransmitter receptors and transporters. This has focus interest on lipid rafts and the notion that these microdomains acts as a kind of signaling platform and thus have an important role in the expression of membrane receptor-mediated signal transduction, cancer, immune responses, neurotransmission, viral infections and various other phenomena due to specific and efficient signaling according to extracellular stimuli. However, the real structure of lipid rafts has not been observed so far due to its small size and a lack of sufficiently sophisticated observation systems. A soft X-ray microscope using a coherent soft X-ray laser in the water window region (2.3–4.4 nm) should prove to be a most powerful tool to observe the dynamic structure of lipid rafts of several tens of nanometers in size in living cells. We have developed for the X-ray microscope a new compact soft X-ray laser using strongly induced plasma high harmonic resonance. We have also developed a time-resolved highly sensitive fluorescence resonance energy transfer (FRET) system and confirmed protein-protein interactions coupled with ligands. The simultaneous use of these new tools for observation of localization of G-protein coupled receptors (GPCRs) in rafts has become an important and optimum tool system to analyze the dynamics of signal transduction through rafts as signaling platform. New technology to visualize rafts is expected to lead to the understanding of those dynamics and innovative development of drug discovery that targets GPCRs localized in lipid rafts. Full article
(This article belongs to the Special Issue GPCR Based Drug Discovery)
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690 KiB  
Review
Functional Consequences of GPCR Heterodimerization: GPCRs as Allosteric Modulators
by Karla K.V. Haack and Nael A. McCarty
Pharmaceuticals 2011, 4(3), 509-523; https://0-doi-org.brum.beds.ac.uk/10.3390/ph4030509 - 14 Mar 2011
Cited by 19 | Viewed by 9486
Abstract
G Protein Coupled Receptors (GPCRs) represent the largest family of membrane proteins in the human genome, are the targets of approximately 25% of all marketed pharmaceuticals, and the focus of intensive research worldwide given that this superfamily of receptors is as varied in [...] Read more.
G Protein Coupled Receptors (GPCRs) represent the largest family of membrane proteins in the human genome, are the targets of approximately 25% of all marketed pharmaceuticals, and the focus of intensive research worldwide given that this superfamily of receptors is as varied in function as it is ubiquitously expressed among all cell types. Increasing evidence has shown that the classical two part model of GPCR signaling (one GPCR, one type of heterotrimeric G protein) is grossly oversimplified as many GPCRs can couple to more than one type of G protein, each subunit of the heterotrimeric G protein can activate different downstream effectors, and, surprisingly, other GPCRs can affect receptor behavior in G protein-independent ways. The concept of GPCR heterodimerization, or the physical association of two different types of GPCRs, presents an unexpected mechanism for GPCR regulation and function, and provides a novel target for pharmaceuticals. Here we present a synopsis of the functional consequences of GPCR heterodimerization in both in vitro and in vivo studies, focusing on the concept of GPCRs as allosteric modulators. Typically, an allosteric modulator is a ligand or molecule that alters a receptor’s innate functional properties, but here we propose that in the case of GPCR heterodimers, it is the physical coupling of two receptors that leads to changes in cognate receptor signaling. Full article
(This article belongs to the Special Issue GPCR Based Drug Discovery)
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Article
RNA Detection in Live Bacterial Cells Using Fluorescent Protein Complementation Triggered by Interaction of Two RNA Aptamers with Two RNA-Binding Peptides
by Hung-Wei Yiu, Vadim V. Demidov, Paul Toran, Charles R. Cantor and Natalia E. Broude
Pharmaceuticals 2011, 4(3), 494-508; https://0-doi-org.brum.beds.ac.uk/10.3390/ph4030494 - 10 Mar 2011
Cited by 23 | Viewed by 11527
Abstract
Many genetic and infectious diseases can be targeted at the RNA level as RNA is more accessible than DNA. We seek to develop new approaches for detection and tracking RNA in live cells, which is necessary for RNA-based diagnostics and therapy. We recently [...] Read more.
Many genetic and infectious diseases can be targeted at the RNA level as RNA is more accessible than DNA. We seek to develop new approaches for detection and tracking RNA in live cells, which is necessary for RNA-based diagnostics and therapy. We recently described a method for RNA visualization in live bacterial cells based on fluorescent protein complementation [1-3]. The RNA is tagged with an RNA aptamer that binds an RNA-binding protein with high affinity. This RNA-binding protein is expressed as two split fragments fused to the fragments of a split fluorescent protein. In the presence of RNA the fragments of the RNA-binding protein bind the aptamer and bring together the fragments of the fluorescent protein, which results in its re-assembly and fluorescence development [1-3]. Here we describe a new version of the RNA labeling method where fluorescent protein complementation is triggered by paired interactions of two different closely-positioned RNA aptamers with two different RNA-binding viral peptides. The new method, which has been developed in bacteria as a model system, uses a smaller ribonucleoprotein complementation complex, as compared with the method using split RNA-binding protein, and it can potentially be applied to a broad variety of RNA targets in both prokaryotic and eukaryotic cells. We also describe experiments exploring background fluorescence in these RNA detection systems and conditions that improve the signal-to-background ratio. Full article
(This article belongs to the Special Issue Aptamer-Based Therapeutics)
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236 KiB  
Opinion
Neuropeptide Receptors: Novel Targets for HIV/AIDS Therapeutics
by Donald R. Branch
Pharmaceuticals 2011, 4(3), 485-493; https://0-doi-org.brum.beds.ac.uk/10.3390/ph4030485 - 09 Mar 2011
Cited by 3 | Viewed by 8074
Abstract
The vasoactive intestinal peptide/pituitary adenylyl cyclase-activating polypepetide (VPAC) receptors are important for many physiologic functions, including glucose homeostasis, neuroprotection, memory, gut function, modulation of the immune system and circadian function. In addition, VPAC receptors have been shown to function in vitro to modulate [...] Read more.
The vasoactive intestinal peptide/pituitary adenylyl cyclase-activating polypepetide (VPAC) receptors are important for many physiologic functions, including glucose homeostasis, neuroprotection, memory, gut function, modulation of the immune system and circadian function. In addition, VPAC receptors have been shown to function in vitro to modulate the infection of HIV by a signal transduction pathway that appears to regulate viral integration. In this article, the affects of VPAC stimulation on HIV infection will be reviewed and approaches for the development of HIV/AIDS therapeutics that target these receptors will be described. Novel HIV/AIDS therapeutics are urgently required to stem the continued spread of this disease, particularly in underdeveloped countries. Drug design to inhibit signaling through VPAC1 and stimulate signaling through VPAC2 could lead to alternative therapies for the treatment and/or prevention of HIV/AIDS. Full article
(This article belongs to the Special Issue GPCR Based Drug Discovery)
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209 KiB  
Review
Myocardial Opioid Receptors in Conditioning and Cytoprotection
by Grant Williams-Pritchard, John P. Headrick and Jason N. Peart
Pharmaceuticals 2011, 4(3), 470-484; https://0-doi-org.brum.beds.ac.uk/10.3390/ph4030470 - 04 Mar 2011
Cited by 7 | Viewed by 7749
Abstract
Opioid compounds and G-protein coupled opioid receptors (ORs) have been studied widely in terms of central nervous system (CNS) actions relating to pain management and drug abuse. Opioids are also linked to induction of mammalian hibernation, a natural state of tolerance involving prolonged [...] Read more.
Opioid compounds and G-protein coupled opioid receptors (ORs) have been studied widely in terms of central nervous system (CNS) actions relating to pain management and drug abuse. Opioids are also linked to induction of mammalian hibernation, a natural state of tolerance involving prolonged and orchestrated shifts in cellular metabolism, growth and stress resistance. It is not surprising then that OR agonism induces acute or delayed cytoprotective states in myocardium, rendering ORs an attractive target for protection of cardiac tissue from the potentially fatal consequences of ischemic heart disease. Cardiac ORs are implicated in triggering/mediating so-called ‘conditioning’ responses, in which powerful cytoprotection arises following transient receptor ligation prior to or immediately following ischemic insult. These responses involve one or more OR sub-types engaging pro-survival kinase cascades to ultimately modulate cell stress and mitochondrial end-effectors. However, important questions remain regarding the role of endogenous opioids, OR signalling, and the transduction and mediation of these protective responses. We briefly review opioid-mediated cardioprotection, focussing on recent developments in signal transduction, the role of receptor ‘cross-talk’, and the effects of sustained OR ligand activation. Full article
(This article belongs to the Special Issue Opioids)
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1028 KiB  
Article
Dual-Color Bioluminescence Analysis for Quantitatively Monitoring G-Protein-Coupled Receptor and β-Arrestin Interactions
by A.K.M. Kafi, Mitsuru Hattori, Naomi Misawa and Takeaki Ozawa
Pharmaceuticals 2011, 4(3), 457-469; https://0-doi-org.brum.beds.ac.uk/10.3390/ph4030457 - 25 Feb 2011
Cited by 8 | Viewed by 8902
Abstract
G protein-coupled receptors (GPCRs) are crucial elements in mammalian signal transduction, and are considered to represent potent drug targets. We have previously developed a GPCR assay system in cultured cells based on complementation of split fragments of click beetle (Pyrearinus termitilluminans) [...] Read more.
G protein-coupled receptors (GPCRs) are crucial elements in mammalian signal transduction, and are considered to represent potent drug targets. We have previously developed a GPCR assay system in cultured cells based on complementation of split fragments of click beetle (Pyrearinus termitilluminans) luciferase. The interaction of GPCRs with its target, β-arrestin, resulted in strong emission of bioluminescence upon stimulation with its specific ligand. In this study, we improved precision of the GPCR assay system by using railroad worm (Phrixothrix hirtus) luciferase as an internal control. We generated stable cell lines harboring the railroad worm luciferase and quantitatively evaluate the extent of GPCR-β-arrestin interactions. We showed concentration-dependent bioluminescence responses for four GPCRs: β2-adrenoceptor, endothelin receptor type A, α2-adrenoceptor and human μ-opioid receptor. We also demonstrated that the variation of responses was reduced significantly by normalizing the data with bioluminescence from railroad worm luciferase. This assay system represents a simple and reliable approach for screening drug candidates in a high throughput manner. Full article
(This article belongs to the Special Issue GPCR Based Drug Discovery)
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644 KiB  
Review
Mitochondrial Dysfunction and Oxidative Stress in Asthma: Implications for Mitochondria-Targeted Antioxidant Therapeutics
by P. Hemachandra Reddy
Pharmaceuticals 2011, 4(3), 429-456; https://0-doi-org.brum.beds.ac.uk/10.3390/ph4030429 - 25 Feb 2011
Cited by 99 | Viewed by 13349
Abstract
Asthma is a complex, inflammatory disorder characterized by airflow obstruction of variable degrees, bronchial hyper-responsiveness, and airway inflammation. Asthma is caused by environmental factors and a combination of genetic and environmental stimuli. Genetic studies have revealed that multiple loci are involved in the [...] Read more.
Asthma is a complex, inflammatory disorder characterized by airflow obstruction of variable degrees, bronchial hyper-responsiveness, and airway inflammation. Asthma is caused by environmental factors and a combination of genetic and environmental stimuli. Genetic studies have revealed that multiple loci are involved in the etiology of asthma. Recent cellular, molecular, and animal-model studies have revealed several cellular events that are involved in the progression of asthma, including: increased Th2 cytokines leading to the recruitment of inflammatory cells to the airway, and an increase in the production of reactive oxygen species and mitochondrial dysfunction in the activated inflammatory cells, leading to tissue injury in the bronchial epithelium. Further, aging and animal model studies have revealed that mitochondrial dysfunction and oxidative stress are involved and play a large role in asthma. Recent studies using experimental allergic asthmatic mouse models and peripheral cells and tissues from asthmatic humans have revealed antioxidants as promising treatments for people with asthma. This article summarizes the latest research findings on the involvement of inflammatory changes, and mitochondrial dysfunction/oxidative stress in the development and progression of asthma. This article also addresses the relationship between aging and age-related immunity in triggering asthma, the antioxidant therapeutic strategies in treating people with asthma. Full article
(This article belongs to the Special Issue Genes, Mechanisms and Drugs for Asthma)
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