Articles: human.
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Biotechnology advances · Dec 2013
ReviewAn overview of the diverse roles of G-protein coupled receptors (GPCRs) in the pathophysiology of various human diseases.
G-protein coupled receptors (GPCRs) modulate diverse cellular responses to the majority of neurotransmitters and hormones within the human body. They exhibit much structural and functional diversity, and are responsive to a plethora of endogenous (biogenic amines, cations, lipids, peptides, and glycoproteins) and exogenous (therapeutic drugs, photons, tastants, and odorants) ligands and stimuli. ⋯ The pace of discovery of new GPCR-based drugs has recently accelerated due to rapid advancements in high-resolution structure determination, high-throughput screening technology and in silico computational modeling of GPCR binding interaction with potential drug molecules. This review aims to provide an overview of the diverse roles of GPCRs in the pathophysiology of various diseases that are the major focus of biopharmaceutical research as potential drug targets.
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Activation of glial cells and neuro-glial interactions are emerging as key mechanisms underlying chronic pain. Accumulating evidence has implicated 3 types of glial cells in the development and maintenance of chronic pain: microglia and astrocytes of the central nervous system (CNS), and satellite glial cells of the dorsal root and trigeminal ganglia. Painful syndromes are associated with different glial activation states: (1) glial reaction (ie, upregulation of glial markers such as IBA1 and glial fibrillary acidic protein (GFAP) and/or morphological changes, including hypertrophy, proliferation, and modifications of glial networks); (2) phosphorylation of mitogen-activated protein kinase signaling pathways; (3) upregulation of adenosine triphosphate and chemokine receptors and hemichannels and downregulation of glutamate transporters; and (4) synthesis and release of glial mediators (eg, cytokines, chemokines, growth factors, and proteases) to the extracellular space. ⋯ Glial activation also occurs in acute pain conditions, and acute opioid treatment activates peripheral glia to mask opioid analgesia. Thus, chronic pain could be a result of "gliopathy," that is, dysregulation of glial functions in the central and peripheral nervous system. In this review, we provide an update on recent advances and discuss remaining questions.
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Although plentiful data are available regarding mental states involving the dominant-right arm, the evidence for the nondominant-left arm is sparse. Here, we investigated whether right-handers can generate accurate predictions with either the right or the left arm. Fifteen adults carried out actual and mental arm movements in two directions with varying inertial resistance (inertial anisotropy phenomenon). ⋯ Furthermore, motor-evoked potentials enhancement in both right and left biceps brachii during mental actions indicated that subjects were actively engaged in mental movement simulation and that the disadvantage of the left arm cannot be attributed to the nonactivation of the right motor cortex. Our findings suggest that predictive mechanisms are more robust for the right than the left arm in right-handers. We discussed these findings from the perspective of the internal models theory and the dynamic-dominance hypothesis of laterality.
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Catechol-O-methyltransferase (COMT) metabolizes catecholamines in different tissues. Polymorphisms in COMT gene can attenuate COMT activity and increase sensitivity to pain. Human studies exploring the effect of COMT polymorphisms on pain sensitivity have mostly included small, heterogeneous samples and have ignored several important single nucleotide polymorphisms (SNPs). This study examines the effect of COMT polymorphisms on experimental and postoperative pain phenotypes in a large ethnically homogeneous female patient cohort. ⋯ SNPs rs887200 and rs165774 located in the untranslated regions of the gene had the strongest effects on pain sensitivity. Their effect on pain is described here for the first time. These results should be confirmed in further studies and the potential functional mechanisms of the variants studied.
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The aim of this article is to describe the current and potential clinical translation of pharmacological inhibitors of poly(ADP-ribose) polymerase (PARP) for the therapy of various diseases. The first section of the present review summarizes the available preclinical and clinical data with PARP inhibitors in various forms of cancer. In this context, the role of PARP in single-strand DNA break repair is relevant, leading to replication-associated lesions that cannot be repaired if homologous recombination repair (HRR) is defective, and the synthetic lethality of PARP inhibitors in HRR-defective cancer. ⋯ In these disease indications, PARP overactivation due to oxidative and nitrative stress drives cell necrosis and pro-inflammatory gene expression, which contributes to disease pathology. Accordingly, multiple lines of preclinical data indicate the efficacy of PARP inhibitors to preserve viable tissue and to down-regulate inflammatory responses. As the clinical trials with PARP inhibitors in various forms of cancer progress, it is hoped that a second line of clinical investigations, aimed at testing of PARP inhibitors for various non-oncologic indications, will be initiated, as well.