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Current Opinion in Pharmacology

Friedrich Koch-Nolte, Anna Eichhoff, Carolina Pinto-Espinoza, Nicole Schwarz, Tobias Schäfer, Stephan Menzel, Friedrich Haag, Mélanie Demeules, Henri Gondé, Sahil Adriouch
Targeting the P2X7 ion channel, a danger sensor for extracellular nucleotides, improves outcomes in models of inflammation, cancer, and brain-diseases. Antibodies and nanobodies have been developed that antagonize or potentiate gating of P2X7. Their potential advantages over small-molecule drugs include high specificity, lower off-target effects, and tunable in vivo half-life. Genetic fusion of P2X7-specific biologics to binding modules may enable targeting of specific cell subsets. Besides directly modulating P2X7 function, antibodies can also initiate specific depletion of P2X7-expressing cells...
April 12, 2019: Current Opinion in Pharmacology
Timothy V Murphy, Shaun L Sandow
Localized, oscillating Ca2+ signals have been identified in discrete microdomains of vascular endothelial cells. At myoendothelial contacts (between endothelial and smooth muscle cells), both endothelial Ca2+ pulsars (IP3 -mediated release of intracellular Ca2+ ) and Ca2+ sparklets (extracellular Ca2+ entry via TRP channels) contribute to endothelium-dependent hyperpolarization of smooth muscle, vasodilation, and feedback control of vasoconstriction. Ca2+ sparklets occurring at close-contact domains between endothelial cells are possibly involved in conducted hyperpolarization and spreading vasodilation in arterial networks...
April 12, 2019: Current Opinion in Pharmacology
Asli Bilgic Temel, Dedee F Murrell
This is an updated review of the literature on the emerging therapeutic options for the treatment of pemphigus to provide better care for patients. There is an increasing range of molecules targeted for pemphigus therapy against CD20, Bruton tyrosine kinase, chimeric antigen receptor, T-cell immune components, B-cell activating factor, proliferation-inducing ligand (APRIL), CD25, p38 mitogen-activated protein kinase (p38MAPK) and cytokine modulation therapies (anti-IL-4, anti-IL-6). The main aim of the current new therapies is to provide specific pathology-focused therapeutic options which have long-term sustainable therapeutic effects on disease progress, cause less side effects without systemic immunosuppression, and have less risk of getting antibodies against the medication during treatment...
April 8, 2019: Current Opinion in Pharmacology
Elisa Principi, Lizzia Raffaghello
Myeloid derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells expanded and recruited from the bone marrow to the periphery or to a specific site of inflammation/infection. MDSC have been described in different pathological conditions including cancer, infections, autoimmunity and obesity. The main function of MDSC is immunosuppression occurring through different mechanisms such as induction of immunosuppressive cells, impairment of lymphocyte homing, free radical production, depletion of amino acids critical for T cell functions, upregulation of ectoenzymes involved in adenosine production and activation of immune regulatory molecules responsible of T cell anergy...
April 5, 2019: Current Opinion in Pharmacology
Giulia Guidotti, Liliana Brambilla, Daniela Rossi
Peptides have emerged as novel and promising medicaments for the treatment of many human diseases, including tumors. In the treatment of cancer, they can be employed directly as bioactive therapeutics, promoting the reduction of tumor growth, but also as drug delivery systems, to facilitate the passage of drugs through cell and tissue barriers and to increase the selectivity of therapeutics for tumor cells. The advantages of peptides over standard chemotherapeutic agents are several-fold and include ease of synthesis, high efficacy, reduced side-effects, and low production cost...
April 4, 2019: Current Opinion in Pharmacology
Niklas Rye Jørgensen
Osteoclasts are cells of the hematopoietic lineage that are responsible for bone resorption. Their activity is crucial in the initiation of bone remodeling and for maintenance of a strong and healthy skeleton. However, in a number of diseases, including inflammatory disorders, inappropriately high osteoclast activity results in excessive bone degradation, bone loss, and subsequently fractures. A range of P2X purinergic receptors are expressed in bone cells, and osteoclasts express most of the P2X receptors...
April 4, 2019: Current Opinion in Pharmacology
Anna Solini, Ivana Novak
P2X7 receptors can be found in many tissues and organs, where they mediate several biological functions. This review summarizes the current knowledge about the role of this receptor in the pathogenesis of type 2 diabetes, in which the key clinical features are impaired insulin secretion and sensitivity, hyperglycemia, coexistence of other cardiovascular risk factors such as dyslipidemia and hypertension, and subclinical inflammation. The receptor modulates crucial pathways in the pancreatic islets (where it can either exert a trophic or detrimental action on β cells), and in the liver, in the adipose tissue and in the skeletal muscle, which are main sites of insulin resistance...
April 4, 2019: Current Opinion in Pharmacology
Cristina Alarcón-Vila, Malvina Pizzuto, Pablo Pelegrín
The inflammatory response is regulated by the production of different extracellular mediators, including lipids and extracellular nucleotides. In the extracellular environment, intermediate lipids activate specific G-protein-coupled receptors (GPCRs) in target cells and promote cell recruitment and activation. Extracellular nucleotides activate two types of receptors, the ionotropic purinergic P2X and the metabotropic purinergic P2Y receptors, inducing the release of cytokines and promoting cell recruitment...
April 2, 2019: Current Opinion in Pharmacology
Juan F Martín, Paloma Liras
Numerous microbial communities live in soil, aquatic habitats, plants, and animal bodies. Microbial genome sequences have revealed that thousands of biosynthetic gene clusters (BGCs) are present in different bacteria and filamentous fungi. Many of these BGCs are not expressed in pure cultures in the laboratory. However, a large part of these silent clusters is expressed in nature when complex microbial populations are studied. The encoding specialized metabolites are frequently produced at very low concentrations but still they serve as communication signals that produce important biochemical and differentiation effects on other microorganisms of the consortium...
March 29, 2019: Current Opinion in Pharmacology
Nidia Maldonado-Carmona, Melissa Vázquez-Hernández, Osiris Jair Patiño Chávez, Stefany Daniela Rodríguez-Luna, Omar Jiménez Rodríguez, Sergio Sanchez, Corina Diana Ceapă
New anti-infective drugs are an unmet necessity of modern medicine. The use of ∼omics technologies has exponentially increased the knowledge on active anti-infective structures, where to search for them and their mechanisms of action. Research involving extreme and unique environments (such as endophytes) revealed their potential for many yet unknown active molecules. This work intends to review a recent research involving discovery of secondary metabolites with an established anti-infective action which was mediated by one of the ∼omics sciences: genomics, proteomics, transcriptomics, metabolomics, glycomics or their combinations, as well as the software at the base of these discoveries...
March 25, 2019: Current Opinion in Pharmacology
Luca Antonioli, Corrado Blandizzi, Matteo Fornai, Pál Pacher, H Thomas Lee, György Haskó
Sepsis is life-threatening systemic organ dysfunction caused by a deregulated host response to an infectious insult. Currently, the treatment of sepsis is limited to the use of antibiotics, fluids, and cardiovascular/respiratory support. Despite these interventions, septic mortality remains high, with reduced life quality in survivors. For this reason, the identification of novel drug targets is a pressing task of modern pharmacology. According to a recent research, it appears that P2 purinergic receptors, which can regulate the host's response to infections, have been identified as potential targets for the treatment of sepsis...
March 25, 2019: Current Opinion in Pharmacology
Elena Adinolfi, Elena De Marchi, Elisa Orioli, Anna Pegoraro, Francesco Di Virgilio
Inflammation is constantly associated to cancer. Malignant tumors often develop at sites of chronic inflammation, and inflammation promotes tumor progression. But, at the same time, inflammation is crucial for anti-tumor immune response. Many factors are responsible for this 'Dr Jekyll/Mr Hyde' roles of inflammation, among which one that is attracting increasing attention is the P2X7 receptor (P2X7R). This receptor is expressed by most malignant tumors and widely diffused in innate and adaptive immune cells, where it supports proliferation, chemotaxis, growth factor, and cytokine release...
March 25, 2019: Current Opinion in Pharmacology
Luiz Eduardo Baggio Savio, Robson Coutinho-Silva
Adenosine triphosphate (ATP) is released from host cells during parasite infections and acts as a danger signal in the extracellular space by activating plasma membrane purinergic type 2 receptors-P2 receptors. The activation of these receptors has been described as a crucial step in immune cell activation, inflammation and parasite control. The P2X7 receptor is most involved in the activation of host microbicidal mechanisms, including production of reactive oxygen and nitrogen species, phagolysosomal fusion, acidification of parasitophorous vacuoles and release of cytokines and chemokines...
March 19, 2019: Current Opinion in Pharmacology
Francesca Graziano, Elisa Vicenzi, Guido Poli
HIV-1 infects CD4+ T lymphocytes with a 'helper' function and myeloid cells, mostly tissue-resident macrophages. While infection of CD4 T lymphocytes in the absence of combination antiretroviral therapy (cART) leads to their depletion and to a profound immunodeficiency, macrophages are resistant to virus-induced cytopathicity and are a source of infectious virus, particularly in the central nervous system (CNS). Infected macrophages are characterized by accumulating newly formed viral particles (virions) in subcellular vacuoles defined as 'virus-containing compartments (VCC)', derived from invaginations of the plasma membrane, that are poorly accessible to antiretroviral agents and anti-HIV antibodies...
March 19, 2019: Current Opinion in Pharmacology
Dariusz C Górecki
Mutations in the dystrophin and sarcoglycans genes result in muscular dystrophies causing severe disability and premature death and where no effective treatment is available. New therapeutic approaches targeting secondary disease mechanisms have a strong translational potential. Dystrophic muscle damage triggers release of ATP whilst loss of ecto-ATPase activity of sarcoglycan further elevates extracellular ATP (eATP) levels. Such a high eATP activates P2X7 purinoceptors on immune cells; these contribute to chronic inflammatory and immune responses that exacerbate the dystrophic pathology...
March 19, 2019: Current Opinion in Pharmacology
Kazuhide Inoue
Neuropathic pain is the most important type of chronic pain because it is refractory to available medications. Neuropathic pain occurs after peripheral nerve injury (PNI) or nerve damage by various reasons. In recent decades, a growing body of evidence shows that spinal microglia and P2X4 receptor (P2X4R), a subtype of ionotropic ATP receptors, play a principal role in evoking this pain. Understanding the functions of microglial P2X4R in evoking this pain provides potential strategies for developing new treatments for neuropathic pain...
March 14, 2019: Current Opinion in Pharmacology
David G Trist
No abstract text is available yet for this article.
March 13, 2019: Current Opinion in Pharmacology
Ina Vorberg, Roberto Chiesa
Prion diseases are devastating neurodegenerative disorders for which no drugs are available. The successful development of therapeutics depends on drug screening platforms and preclinical models that recapitulate key molecular and pathological features of the disease. Innovative experimental tools have been developed over the last few years that might facilitate drug discovery, including cell-free prion replication assays and prion-infected flies. However, there is still room for improvement. Animal models of genetic prion disease are few, and only partially recapitulate the complexity of the human disorder...
March 13, 2019: Current Opinion in Pharmacology
Kaido Kurrikoff, David Aphkhazava, Ülo Langel
Peptides hold great potential for the cancer therapy and diagnostics. In the current review, the main and most influential areas of peptide cancer therapeutics are overviewed. These include the development of anticancer peptides, use of peptides for drug delivery, and cancer targeting.
March 8, 2019: Current Opinion in Pharmacology
Marta Calvo Tardón, Mathilde Allard, Valérie Dutoit, Pierre-Yves Dietrich, Paul R Walker
Cancer vaccines based on synthetic peptides are a safe, well-tolerated immunotherapy able to specifically stimulate tumor-reactive T cells. However, their clinical efficacy does not approach that achieved with other immunotherapies such as immune checkpoint blockade. Nevertheless, major advances have been made in selecting tumor antigens to target, identifying epitopes binding to classical and non-classical HLA molecules, and incorporating these into optimal sized peptides for formulation into a vaccine. Limited potency of currently used adjuvants and the immunosuppressive tumor microenvironment are now understood to be major impediments to vaccine efficacy that need to be overcome...
March 1, 2019: Current Opinion in Pharmacology
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