1,721,008 research outputs found
Monitoring opioid receptor interaction in living cells by bioluminescence resonance energy transfer (bret)
No full textBioluminescence resonance energy transfer (BRET) is a natural phenomenon that has been successfully applied for the study of protein–protein interactions, including opioid receptor oligomers. The discovery of opioid receptor homomers and heteromers has brought to the discovery of new functions and new way of signaling and trafficking; therefore, opioid receptor oligomers may be considered as novel drug targets. Fusing receptors of interest with Renilla luciferase and with a fluorescent protein (such as EYFP) it is possible to study opioid receptor dimerization using BRET
An in vitro assay to study the role of opioids in modulating immune cell adhesion
No full textOpioids play a pivotal role in pain transmission but are also able to modulate immune cell functions. In the last decades a connection between opioids and integrins—adhesion molecules involved, among many other processes, in leukocyte recruitment at inflamed site—has been established. To study immune cell integrin-mediated adhesion, cell adhesion assay is a simple, reproducible, and valuable tool capable of unraveling concentration-dependent effects of a test candidate on integrin-mediated cell adhesion
Experimental Pharmacotherapy for Dry Eye Disease: A Review
Full text linkMonica Baiula, Santi Spampinato Department of Pharmacy and Biotechnology, University of Bologna, Bologna, ItalyCorrespondence: Santi SpampinatoDepartment of Pharmacy and Biotechnology, University of Bologna, via Irnerio 48, Bologna, ItalyTel +39 0512091851Email [email protected]: Dry eye disease (DED) is a complex multifactorial disease showing heterogenous symptoms, including dryness, photophobia, ocular discomfort, irritation and burning but also pain. These symptoms can affect visual function leading to restrictions in daily life activities and reduction in work productivity with a consequently high impact on quality of life. Several pathological mechanisms contribute to the disease: evaporative water loss leads to impairment and loss of tear homeostasis inducing either directly or indirectly to inflammation, in a self-perpetuating vicious cycle. Dysregulated ocular immune responses result in ocular surface damage, which further contributes to DED pathogenesis. Currently, DED treatment is based on a flexible stepwise approach to identify the most beneficial intervention. Although most of the available treatments may control to a certain extent some signs and symptoms of DED, they show significant limitations and do not completely address the needs of patients suffering from DED. This review provides an overview of the emerging experimental therapies for DED. Several promising therapeutic strategies are under development with the aim of dampening inflammation and restoring the homeostasis of the ocular surface microenvironment. Results from early phase clinical trials, testing the effects of EnaC blockers, TRPM8 agonist or mesenchymal stem cells in DED patients, are especially awaited to demonstrate their therapeutic value for the treatment of DED. Moreover, the most advanced experimental strategies in the pipeline for DED, tivanisiran, IL-1R antagonist EBI-005 and SkQ1, are being tested in Phase III clinical trials, still ongoing. Nevertheless, although promising results, further studies are still needed to confirm efficacy and safety of the new emerging therapies for DED.Keywords: dry eye disease, inflammation, tivanisiran, IL-1R antagonist, SkQ
Contribution of alpha(4)beta(1) integrin to the antiallergic effect of levocabastine.
No full textBiochem Pharmacol. 2008 Sep 15;76(6):751-62. Epub 2008 Jul 15.
Contribution of alpha4beta1 integrin to the antiallergic effect of levocabastine.
Qasem AR, Bucolo C, Baiula M, Spartà A, Govoni P, Bedini A, Fascì D, Spampinato S.
Source
Department of Medicine, Health Science Campus, University of Toledo, OH, USA.
Abstract
Levocabastine is an antiallergic drug acting as a histamine H1-receptor antagonist. In allergic conjunctivitis (AC), it may also antagonize up-regulation of the intercellular adhesion molecule-1 (ICAM-1) expressed on epithelial conjunctival cells. However, little is known about its effects on eosinophils, important effector cells in AC. The adhesion molecule integrin alpha(4)beta(1) is expressed in eosinophils; it interacts with the vascular cell adhesion molecule-1 (VCAM-1) and fibronectin (FN) in vascular endothelial cells and contributes to eosinophil activation and infiltration in AC. This study provides evidence that in a scintillation proximity assay levocabastine (IC(50) 406 microM), but not the first-generation antihistamine chlorpheniramine, displaced (125)I-FN binding to human integrin alpha(4)beta(1) and, in flow cytometry analysis, levocabastine antagonized the binding of a primary antibody to integrin alpha(4) expressed on the Jurkat cell surface. Levocabastine, but not chlorpheniramine, binds the alpha(4)beta(1) integrin and prevents eosinophil adhesion to VCAM-1, FN or human umbilical vascular endothelial cells (HUVEC) in vitro. Similarly, levocabastine affects alpha(L)beta(2)/ICAM-1-mediated adhesion of Jurkat cells. In a model of AC levocabastine eye drops reduced the clinical aspects of the late-phase reaction and the conjunctival expression of alpha(4)beta(1) integrin by reducing infiltrated eosinophils. We propose that blockade of integrin-mediated cell adhesion might be a target of the antiallergic action of levocabastine and may play a role in preventing eosinophil adhesion and infiltration in AC
Novel Ligands Targeting alpha(4)beta(1) Integrin: Therapeutic Applications and Perspectives
No full textAmong the other members of the adhesion molecules’ family, α4β1 integrin,
a heterodimeric receptor, plays a crucial role in inflammatory diseases, cancer
development, metastasis and stem cell mobilization or retention. In many cases,
its function in pathogenesis is not yet completely understood and investigations on
ligand binding and related stabilization of active/inactive conformations still represent
an important goal. For this reason, starting from the highlight of α4β1 functions in
human pathologies, we report an overview of synthetic α4β1 integrin ligands under
development as potential therapeutic agents. The small molecule library that we have
selected represents a collection of lead compounds. These molecules are the object of
future refinement in academic and industrial research, in order to achieve a fine tuning
of α4β1 integrin regulation for the development of novel agents against pathologies still
eluding an effective solution
Editorial: Integrin Ligands and Their Bioconjugate Systems: Synthesis, Conformation, and Biological Activity
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Quantitative Systems Pharmacology and Biased Agonism at Opioid Receptors: A Potential Avenue for Improved Analgesics
Full text linkChronic pain is debilitating and represents a significant burden in terms of personal and socio-economic costs. Although opioid analgesics are widely used in chronic pain treatment, many patients report inadequate pain relief or relevant adverse effects, highlighting the need to develop analgesics with improved efficacy/safety. Multiple evidence suggests that G protein-dependent signaling triggers opioid-induced antinociception, whereas arrestin-mediated pathways are credited with modulating different opioid adverse effects, thus spurring extensive research for G protein-biased opioid agonists as analgesic candidates with improved pharmacology. Despite the increasing expectations of functional selectivity, translating G protein-biased opioid agonists into improved therapeutics is far from being fully achieved, due to the complex, multidimensional pharmacology of opioid receptors. The multifaceted network of signaling events and molecular processes underlying therapeutic and adverse effects induced by opioids is more complex than the mere dichotomy between G protein and arrestin and requires more comprehensive, integrated, network-centric approaches to be fully dissected. Quantitative Systems Pharmacology (QSP) models employing multidimensional assays associated with computational tools able to analyze large datasets may provide an intriguing approach to go beyond the greater complexity of opioid receptor pharmacology and the current limitations entailing the development of biased opioid agonists as improved analgesics
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