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Pharmacology & Therapeutics

Cindy Barnig, Nelly Frossard, Bruce D Levy
Asthma is a chronic disorder characterized by persistent inflammation of the airways with mucosal infiltration of eosinophils, T lymphocytes, and mast cells, and release of proinflammatory cytokines and lipid mediators. The natural resolution of airway inflammation is now recognized as an active host response, with highly coordinated cellular events under the control of endogenous pro-resolving mediators that enable the restoration of tissue homeostasis. Lead members of proresolving mediators are enzymatically derived from essential polyunsaturated fatty acids, including arachidonic acid-derived lipoxins, eicosapentaenoic acid-derived E-series resolvins, and docosahexaenoic acid-derived D-series resolvins, protectins, and maresins...
January 17, 2018: Pharmacology & Therapeutics
Eloísa Rubio-Beltrán, Alejandro Labastida-Ramírez, Carlos M Villalón, Antoinette MaassenVanDenBrink
Migraine is a neurovascular disorder that involves activation of the trigeminovascular system and cranial vasodilation mediated by release of calcitonin gene-related peptide (CGRP). The gold standard for acute migraine treatment are the triptans, 5-HT1B/1D/(1F) receptor agonists. Their actions are thought to be mediated through activation of: (i) 5-HT1B receptors in cranial blood vessels with subsequent cranial vasoconstriction; (ii) prejunctional 5-HT1D receptors on trigeminal fibers that inhibit trigeminal CGRP release; and (iii) 5-HT1B/1D/1F receptors in central nervous system involved in (anti)nociceptive modulation...
January 17, 2018: Pharmacology & Therapeutics
Jessica N Blom, Qingping Feng
Despite therapeutic advances that have prolonged life, myocardial infarction (MI) remains a leading cause of death worldwide and imparts a significant economic burden. The advancement of treatments to improve cardiac repair post-MI requires the discovery of new targeted treatment strategies. Recent studies have highlighted the importance of the epicardial covering of the heart in both cardiac development and lower vertebrate cardiac regeneration. The epicardium serves as a source of cardiac cells including smooth muscle cells, endothelial cells and cardiac fibroblasts...
January 17, 2018: Pharmacology & Therapeutics
Matthen Mathew, Thomas Enzler, Catherine A Shu, Naiyer A Rizvi
Antitumor immunity relies on the ability of the immune system to recognize tumor cells as foreign and eliminate them. An effective immune response in this setting is due to surveillance of tumor-specific antigens that induce an adaptive immune response resulting in T-cell mediated cytotoxicity. Immune checkpoint inhibitors, specifically those targeting the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis, have demonstrated promising activity in non-small cell lung cancer (NSCLC). However, there remains a crucial need for better treatment strategies for the majority of patients with advanced NSCLC, particularly in the frontline setting...
January 17, 2018: Pharmacology & Therapeutics
Sang-Bing Ong, Sauri Hernández-Reséndiz, Gustavo E Crespo-Avilan, Regina T Mukhametshina, Xiu-Yi Kwek, Hector A Cabrera-Fuentes, Derek J Hausenloy
Acute myocardial infarction (AMI) and the heart failure that often follows, are major causes of death and disability worldwide. As such, new therapies are required to limit myocardial infarct (MI) size, prevent adverse left ventricular (LV) remodeling, and reduce the onset of heart failure following AMI. The inflammatory response to AMI, plays a critical role in determining MI size, and a persistent pro-inflammatory reaction can contribute to adverse post-MI LV remodeling, making inflammation an important therapeutic target for improving outcomes following AMI...
January 9, 2018: Pharmacology & Therapeutics
Marcello Maugeri-Saccà, Ruggero De Maria
The Hippo pathway is a central regulator of organ size and tissue homeostasis. Hippo kinases and adaptor proteins mediate the phosphorylation and inactivation of YAP and TAZ, two closely related transcription co-activators. The Hippo pathway responds to a variety of extracellular and intracellular signals, spanning from cell-cell contact and mechanical cues to ligands of G-protein-coupled receptors and metabolic avenues. In some instances, YAP/TAZ activation is tuned by forces that bypass the Hippo kinase module, adding further complexity to the biology of the pathway...
January 2, 2018: Pharmacology & Therapeutics
Hiroshi Tsuneki, Tsutomu Wada, Toshiyasu Sasaoka
Sleep, a mysterious behavior, has recently been recognized as a crucial factor for health and longevity. The daily sleep/wake cycle provides the basis of biorhythms controlling whole-body homeostasis and homeodynamics; therefore, disruption of sleep causes several physical and psychological disorders, including cardiovascular disease, obesity, diabetes, cancer, anxiety, depression, and cognitive dysfunction. However, the mechanism linking sleep disturbances and sleep-related disorders remains unknown. Orexin (also known as hypocretin) is a neuropeptide produced in the hypothalamus...
December 28, 2017: Pharmacology & Therapeutics
Hitisha K Patel, Teeru Bihani
Breast cancer is the most frequently diagnosed cancer in women, with estrogen receptor positive (ER+) breast cancer making up approximately 75% of all breast cancers diagnosed. Given the dependence on active ER signaling in these tumors, the predominant treatment strategy has been to inhibit various aspects of this pathway including directly antagonizing ER with the use of selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs). Interestingly, the dependence on ER for breast cancer growth is often retained even after progression through several lines of antiestrogen therapy, making ER a bonafide biomarker for this cancer subtype and driving the continued research and development of novel ER-targeted therapeutics to treat this patient population...
December 28, 2017: Pharmacology & Therapeutics
Andrew T Reid, Punnam Chander Veerati, Reinoud Gosens, Nathan W Bartlett, Peter A Wark, Chris L Grainge, Stephen M Stick, Anthony Kicic, Fatemeh Moheimani, Philip M Hansbro, Darryl A Knight
Dysregulated induction of goblet cell differentiation results in excessive production and retention of mucus and is a common feature of several chronic airways diseases. To date, therapeutic strategies to reduce mucus accumulation have focused primarily on altering the properties of the mucus itself, or have aimed to limit the production of mucus-stimulating cytokines. Here we review the current knowledge of key molecular pathways that are dysregulated during persistent goblet cell differentiation and highlights both pre-existing and novel therapeutic strategies to combat this pathology...
December 26, 2017: Pharmacology & Therapeutics
Elodie Gautier-Veyret, Jean-Louis Pépin, Françoise Stanke-Labesque
Obstructive sleep apnea (OSA) is characterized by recurrent episodes of partial or complete upper airway obstruction, occurring during sleep, leading to chronic intermittent hypoxia (IH), which harms the cardiovascular system. OSA is associated with both functional and structural vascular alterations that contribute to an increased prevalence of fatal and non-fatal cardiovascular events. OSA is a heterogeneous disease with respect to the severity of hypoxia, the presence of daytime symptoms, obesity, and cardiovascular comorbidities...
December 22, 2017: Pharmacology & Therapeutics
Noriko Iwamoto, Takashi Shimada
Since the turn of the century, mass spectrometry (MS) technologies have continued to improve dramatically, and advanced strategies that were impossible a decade ago are increasingly becoming available. The basic characteristics behind these advancements are MS resolution, quantitative accuracy, and information science for appropriate data processing. The spectral data from MS contain various types of information. The benefits of improving the resolution of MS data include accurate molecular structural-derived information, and as a result, we can obtain a refined biomolecular structure determination in a sequential and large-scale manner...
December 21, 2017: Pharmacology & Therapeutics
Giovanny J Martínez-Colón, Bethany B Moore
The body is exposed to foreign pathogens every day, but remarkably, most pathogens are effectively cleared by the innate immune system without the need to invoke the adaptive immune response. Key cellular components of the innate immune system include macrophages and neutrophils and the recruitment and function of these cells are tightly regulated by chemokines and cytokines in the tissue space. Innate immune responses are also known to regulate development of adaptive immune responses often via the secretion of various cytokines...
December 21, 2017: Pharmacology & Therapeutics
Anuradha Krishnamurthy, Antonio Jimeno
The ability to produce monoclonal antibodies with defined and distinct specificities has resulted in a vast spectrum of therapeutic monoclonal antibodies including bispecific antibodies (BsAbs). Several types of BsAbs have been produced but the most well-known of these are trispecific antibodies (TrAbs or TrioMabs) and bispecific T cell engager antibodies (BiTE). TrAbs have two variable segments for antigen binding and an Fc component to recruit immune cells. Catumaxomab is a TrAb that has orphan drug status from the Food and Drug Administration (FDA) for EpCam positive gastric and ovarian tumors and was previously approved by the European Medicinal Agency (EMA) for the same indication...
December 18, 2017: Pharmacology & Therapeutics
Angela R Wild, Mark L Dell'Acqua
A common feature of neurological and neuropsychiatric disorders is a breakdown in the integrity of intracellular signal transduction pathways. Dysregulation of ion channels and receptors in the cell membrane and the enzymatic mediators that link them to intracellular effectors can lead to synaptic dysfunction and neuronal death. However, therapeutic targeting of these ubiquitous signaling elements can lead to off-target side effects due to their widespread expression in multiple systems of the body. A-kinase anchoring proteins (AKAPs) are multivalent scaffolding proteins that compartmentalize a diverse range of receptor and effector proteins to streamline signaling within nanodomain signalosomes...
December 17, 2017: Pharmacology & Therapeutics
Na-Oh Yunn, Jaeyoon Kim, Youndong Kim, Ingo Leibiger, Per-Olof Berggren, Sung Ho Ryu
The insulin receptor is an important regulator of metabolic processes in the body, and in particular of glucose homeostasis, including glucose uptake into peripheral tissues. Thus, insulin administration is an effective treatment for diabetes, which is characterized by chronic elevation of blood glucose. However, insulin is not only a metabolic regulator, but also functions as a growth hormone. Accordingly, studies of long-term insulin administration and of the hyperinsulinemia associated with type 2 diabetes have raised concerns about possible increases in the risks of cancer and atherosclerosis, due to excessive stimulation of cell proliferation...
December 17, 2017: Pharmacology & Therapeutics
Ángel C Roman, José M Carvajal-Gonzalez, Jaime M Merino, Sonia Mulero-Navarro, Pedro M Fernández-Salguero
The aryl hydrocarbon receptor (AhR) is well-known for its major contributions to the cellular responses against environmental toxins and carcinogens. Notably, AhR has also emerged as a key transcription factor controlling many physiological processes including cell proliferation and apoptosis, differentiation, adhesion and migration, pluripotency and stemness. These novel functions have broadened our understanding of the signaling pathways and molecular intermediates interacting with AhR under both homeostatic and pathological conditions...
December 16, 2017: Pharmacology & Therapeutics
Mohammed Akbar, Mark Egli, Young-Eun Cho, Byoung-Joon Song, Antonio Noronha
Patients who suffer from alcohol use disorders (AUDs) usually go through various socio-behavioral and pathophysiological changes that take place in the brain and other organs. Recently, consumption of unhealthy food and excess alcohol along with a sedentary lifestyle has become a norm in both developed and developing countries. Despite the beneficial effects of moderate alcohol consumption, chronic and/or excessive alcohol intake is reported to negatively affect the brain, liver and other organs, resulting in cell death, organ damage/failure and death...
November 27, 2017: Pharmacology & Therapeutics
Lloyd D Fricker, Lakshmi A Devi
Neuropeptides are the largest class of intercellular signaling molecules, contributing to a wide variety of physiological processes. Neuropeptide receptors are therapeutic targets for a broad range of drugs, including medications to treat pain, addiction, sleep disorders, and nausea. In addition to >100 peptides with known functions, many peptides have been identified in mammalian brain for which the cognate receptors have not been identified. Similarly, dozens of "orphan" G protein-coupled receptors have been identified in the mammalian genome...
November 21, 2017: Pharmacology & Therapeutics
Pınar Ö Eser, Pasi A Jänne
Advanced non-small cell lung cancer (NSCLC) continues to be an incurable family of thoracic malignancies that is chronically managed with chemotherapy, targeted therapy, and immunotherapy. While the discovery of driver oncogenes and the advent of targeted and immunotherapies in the last decade have vastly improved clinical disease management for patients harboring druggable mutations, the mainstay treatment for the majority of NSCLC patients remains cytotoxic chemotherapy. The clinical efficacy of targeted, immune, and cytotoxic therapies is limited by the development of drug resistance...
November 10, 2017: Pharmacology & Therapeutics
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