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Handbook of Experimental Pharmacology

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https://www.readbyqxmd.com/read/28871306/introduction-to-sigma-proteins-evolution-of-the-concept-of-sigma-receptors
#1
Felix J Kim
For over 40 years, scientists have endeavored to understand the so-called sigma receptors. During this time, the concept of sigma receptors has continuously and significantly evolved. With thousands of publications on the subject, these proteins have been implicated in various diseases, disorders, and physiological processes. Nevertheless, we are just beginning to understand what sigma proteins do and how they work. Two subtypes have been identified, Sigma1 and Sigma2. Whereas Sigma1 (also known as sigma-1 receptor, Sig1R, σ1 receptor, and several other names) was cloned over 20 years ago, Sigma2 (sigma-2 receptor, σ2 receptor) was cloned very recently and had remained a pharmacologically defined entity...
September 5, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28707143/clinical-sleep-wake-disorders-ii-focus-on-insomnia-and-circadian-rhythm-sleep-disorders
#2
Kai Spiegelhalder, Christoph Nissen, Dieter Riemann
Insomnia and circadian rhythm sleep disorders affect large proportions of the population and have pronounced effects on quality of life and daytime performance. While the neurobiology of insomnia is not yet fully understood, circadian rhythm sleep disorders are assumed to be caused by a mismatch between the individual circadian phase position and the desired sleep-wake schedule. Benzodiazepines and non-benzodiazepine positive allosteric GABAA receptor modulators improve sleep onset and maintenance in the short-term treatment of insomnia...
July 14, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28689302/ligand-directed-signaling-at-the-delta-opioid-receptor
#3
Ana Vicente-Sanchez, Amynah A Pradhan
Delta opioid receptors (δORs) regulate a number of physiological functions, and agonists for this receptor are being pursued for the treatment of mood disorders, chronic pain, and migraine. A major challenge to the development of these compounds is that, like many G-protein coupled receptors (GPCRs), agonists at the δOR can induce very different signaling and receptor trafficking events. This concept, known as ligand-directed signaling, functional selectivity, or biased agonism, can result in different agonists producing highly distinct behavioral consequences...
July 9, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28667477/allosteric-modulation-of-opioid-g-protein-coupled-receptors-by-sigma1-receptors
#4
Gavril W Pasternak
Since their proposal in 1976, the concept of sigma1 receptors has been continually evolving. Initially thought to be a member of the opioid receptor family, molecular studies have now identified its genes and established its structure crystallographically. Much effort has now revealed its importance as a chaperone in the endoplasmic reticulum, but its functions extend beyond this. Sigma1 receptors have been associated with a host of signaling systems. Evidence over the past 20 years has established the modulatory effects of sigma1 ligands on opioid systems...
July 1, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28667476/3d-homology-model-of-sigma1-receptor
#5
Erik Laurini, Domenico Marson, Maurizio Fermeglia, Sabrina Pricl
This chapter presents the three-dimensional (3D) model of the Sigma1 receptor protein as obtained from homology modeling techniques. We show the applicability of this structure to docking-based virtual screening and discuss combined in silico/in vitro mutagenesis studies performed to validate the structural features of the Sigma1 receptor model and to qualify/quantify the prominent role of specific amino acid residues in ligand binding. The validation of the virtual 3D Sigma1 receptor model and its reliable applicability to docking-based virtual screening is of significance for rational ligand design, even in light of the recently reported crystal structure for the Sigma1 receptor...
July 1, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28646346/adenosine-and-sleep
#6
Michael Lazarus, Jiang-Fan Chen, Zhi-Li Huang, Yoshihiro Urade, Bertil B Fredholm
The classic endogenous somnogen adenosine promotes sleep via A1 and A2A receptors. In this chapter, we present an overview of the current knowledge regarding the regulation of adenosine levels, adenosine receptors, and available pharmacologic and genetic tools to manipulate the adenosine system. This is followed by a summary of current knowledge of the role of adenosine and its receptors in the regulation of sleep and wakefulness. Despite strong data implicating numerous brain areas, including the basal forebrain, the tuberomammillary nucleus, the lateral hypothalamus, and the nucleus accumbens, in the adenosinergic control of sleep, the complete neural circuitry in the brain involved in the sleep-promoting effects of adenosine remains unclear...
June 24, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28620761/medicinal-chemistry-of-%C3%AF-1-receptor-ligands-pharmacophore-models-synthesis-structure-affinity-relationships-and-pharmacological-applications
#7
Frauke Weber, Bernhard Wünsch
In the first part of this chapter, we summarize the various pharmacophore models for σ1 receptor ligands. Common to all of them is a basic amine flanked by two hydrophobic regions, representing the pharmacophoric elements. The development of computer-based models like the 3D homology model is described as well as the first crystal structure of the σ1 receptor. The second part focuses on the synthesis and biological properties of different σ1 receptor ligands, identified as 1-9. Monocyclic piperazines 1 and bicyclic piperazines 2 and 3 were developed as cytotoxic compounds, thus the IC50 values of cell growth and survival inhibition studies are given for all derivatives...
June 16, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28510066/the-delta-opioid-receptor-in-pain-control
#8
Khaled Abdallah, Louis Gendron
Nowadays, the delta opioid receptor (DOPr) represents a promising target for the treatment of chronic pain and emotional disorders. Despite the fact that they produce limited antinociceptive effects in healthy animals and in most acute pain models, DOPr agonists have shown efficacy in various chronic pain models. In this chapter, we review the progresses that have been made over the last decades in understanding the role played by DOPr in the control of pain. More specifically, the distribution of DOPr within the central nervous system and along pain pathways is presented...
May 17, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28405776/immune-mediated-and-hypoxia-regulated-programs-accomplices-in-resistance-to-anti-angiogenic-therapies
#9
Diego O Croci, Santiago P Mendez-Huergo, Juan P Cerliani, Gabriel A Rabinovich
In contrast to mechanisms taking place during resistance to chemotherapies or other targeted therapies, compensatory adaptation to angiogenesis blockade does not imply a mutational alteration of genes encoding drug targets or multidrug resistance mechanisms but instead involves intrinsic or acquired activation of compensatory angiogenic pathways. In this article we highlight hypoxia-regulated and immune-mediated mechanisms that converge in endothelial cell programs and preserve angiogenesis in settings of vascular endothelial growth factor (VEGF) blockade...
April 13, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28405775/iron-deficiency-treatment-in-patients-with-heart-failure
#10
Ewa A Jankowska, Marcin Drozd, Piotr Ponikowski
Iron deficiency (ID) is one of the major risk factors for disability and mortality worldwide, and it was identified as a common and ominous comorbidity in patients with heart failure (HF), both with and without anaemia. Based on two clinical trials (FAIR-HF and CONFIRM-HF) and other epidemiological evidence, ID has been recognized as an important therapeutic target in symptomatic patients with HF and LVEF ≤45%.Intravenous iron supplementation has been demonstrated to be safe and effective for iron repletion and related with an improvement in clinical status, exercise capacity, and quality of life...
April 13, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28382470/comorbidities-in-heart-failure
#11
Haye H van der Wal, Vincent M van Deursen, Peter van der Meer, Adriaan A Voors
Comorbidities frequently accompany chronic heart failure (HF), contributing to increased morbidity and mortality, and an impaired quality of life. We describe the prevalence of several high-impact comorbidities in chronic HF patients and their impact on morbidity and mortality. Furthermore, we try to explain the underlying pathophysiological processes and the complex interaction between chronic HF and specific comorbidities. Although common risk factors are likely to contribute, it is reasonable to believe that factors associated with HF might cause other comorbidities and vice versa...
April 6, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28382469/mesenchymal-stem-cell-therapy-for-the-treatment-of-heart-failure-caused-by-ischemic-or-non-ischemic-cardiomyopathy-immunosuppression-and-its-implications
#12
Michael J Lipinski, Dror Luger, Stephen E Epstein
HF patients with signs and symptoms of worsening heart failure (HF), despite optimal medical therapy, have a poor prognosis. The pathways contributing to HF are multiple, probably accounting, in part, for current treatment approaches not being more effective. Stem cells, particularly mesenchymal stem cells (MSCs), have a broad range of activities, making them particularly interesting candidates for a new HF therapeutic. This review presents an overview of the studies examining the efficacy of stem cell studies administered to HF patients, focusing mainly on MSCs...
April 6, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28382467/plasticity-of-resistance-and-sensitivity-to-anti-epidermal-growth-factor-receptor-inhibitors-in-metastatic-colorectal-cancer
#13
Andrea Sartore-Bianchi, Salvatore Siena
Colorectal cancer (CRC) is one of the most prevalent cancers and the second leading cause of cancer mortality worldwide. Survival in the metastatic setting has been gradually improved by the addition to cytotoxic chemotherapy of agents targeting the vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR). Considerable heterogeneity exists within CRC due to the varied genetic and epigenetic mechanisms involved in differing pathways of carcinogenesis. The knowledge of molecular abnormalities underlying colorectal tumourigenesis and the progression of dysplastic precursors to invasive and ultimately metastatic lesions has advanced in recent years by comprehensive sequencing studies...
April 6, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28353036/resistance-to-hormonal-therapy-in-prostate-cancer
#14
Alfredo Berruti, Alberto Dalla Volta
Several therapeutic strategies are actually available in the management of prostate cancer: Targeting the androgen receptor (AR) is the goal both for initial androgen deprivation therapy (ADT) and second-generation androgen ablative agents (abiraterone and enzalutamide). Chemotherapy with taxanes, administered upon progression or as first line approach in association with ADT, is another therapeutic option. Unfortunately, none of these therapies is curative and patients are destined to develop a resistant phenotype...
March 29, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28353035/the-roles-of-opioid-receptors-in-cutaneous-wound-healing
#15
Mei Bigliardi-Qi, Paul Bigliardi
The process of recovery from skin wounding can be protracted and painful, and scarring may lead to weakness of the tissue, unpleasant sensations such as pain or itch, and unfavorable cosmetic outcomes. Moreover, some wounds simply fail to heal and become a chronic burden for the sufferer. Understanding the mechanisms underlying wound healing and the concomitant sensory disorders and how they might be manipulated for therapeutic benefit has attracted much interest in recent years, and here we discuss the latest developments in the field, focusing on the emergent roles of the peripheral opioid receptor (OPr) system...
March 29, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28332049/molecular-and-pharmacological-mechanisms-of-drug-resistance-an-evolving-paradigm
#16
Benedetta Colmegna, Lavinia Morosi, Maurizio D'Incalci
The high heterogeneity and genomic instability of malignant tumors explains why even responsive tumors contain cell clones that are resistant for many possible mechanisms involving intracellular drug inactivation, low uptake or high efflux of anticancer drugs from cancer cells, qualitative or quantitative changes in the drug target. Many tumors, however, are resistant because of insufficient exposure to anticancer drugs, due to pharmacokinetic reasons and inefficient and heterogeneous tumor drug distribution, related to a deficient vascularization and high interstitial pressure...
March 23, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28332048/histamine-release-from-mast-cells-and-basophils
#17
Francesco Borriello, Raffaella Iannone, Gianni Marone
Mast cells and basophils represent the most relevant source of histamine in the immune system. Histamine is stored in cytoplasmic granules along with other amines (e.g., serotonin), proteases, proteoglycans, cytokines/chemokines, and angiogenic factors and rapidly released upon triggering with a variety of stimuli. Moreover, mast cell and basophil histamine release is regulated by several activating and inhibitory receptors. The engagement of different receptors can trigger different modalities of histamine release and degranulation...
March 23, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28332047/mechanisms-of-resistance-to-target-therapies-in-non-small-cell-lung-cancer
#18
Francesco Facchinetti, Claudia Proto, Roberta Minari, Marina Garassino, Marcello Tiseo
Targeted therapies are revolutionizing the treatment of advanced non-small cell lung cancer (NSCLC). The discovery of key oncogenic events mainly in lung adenocarcinoma, like EGFR mutations or ALK rearrangements, has changed the treatment landscape while improving the prognosis of lung cancer patients. Inevitably, virtually all patients initially treated with targeted therapies develop resistance because of the emergence of an insensitive cellular population, selected by pharmacologic pressure. Diverse mechanisms of resistance, in particular to EGFR, ALK and ROS1 tyrosine-kinase inhibitors (TKIs), have now been discovered and may be classified in three different groups: (1) alterations in the target (such as EGFR T790M and ALK or ROS1 mutations); (2) activation of alternative pathways (i...
March 23, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28321587/analytical-methods-for-the-quantification-of-histamine-and-histamine-metabolites
#19
Heike Bähre, Volkhard Kaever
The endogenous metabolite histamine (HA) is synthesized in various mammalian cells but can also be ingested from exogenous sources. It is involved in a plethora of physiological and pathophysiological processes. So far, four different HA receptors (H1R-H4R) have been described and numerous HAR antagonists have been developed. Contemporary investigations regarding the various roles of HA and its main metabolites have been hampered by the lack of highly specific and sensitive analytic methods for all of these analytes...
March 21, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28315073/mechanisms-of-resistance-to-immune-checkpoint-antibodies
#20
Rodrigo N Ramos, Eliane Piaggio, Emanuela Romano
Immunotherapy using checkpoint inhibitors has changed the way we treat several aggressive cancers such as melanoma, non-small cell lung and head & neck cancers, among others, with durable responses achieved in the metastatic setting. However, unfortunately, the vast majority of patients do not respond to checkpoint inhibition therapy and a minority of patients, who do respond to treatment, develop secondary resistance and experience relapse by mechanisms still inadequately understood. Emerging evidence shows that alterations in multiple signaling pathways are involved in primary and/or secondary resistance to checkpoint inhibition...
March 18, 2017: Handbook of Experimental Pharmacology
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