Expert opinion on therapeutic targets
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Expert Opin. Ther. Targets · Jan 2015
ReviewTargeting angiotensin II type 2 receptor pathways to treat neuropathic pain and inflammatory pain.
Neuropathic pain and chronic inflammatory pain are large unmet medical needs. Over the past two decades, numerous 'pain targets' have been identified for analgesic drug discovery. Despite promising results in rodent pain models, many compounds modulating such targets lacked efficacy in clinical trials. An exception is oral EMA401, a small-molecule angiotensin II type 2 receptor (AT2R) antagonist. ⋯ The functional importance of angiotensin II/AT2R signaling has remained enigmatic for decades, and there are no clinically available medications that target the AT2R. However, on the basis of preclinical findings and recent clinical trial data showing that the peripherally restricted, small-molecule AT2R antagonist, EMA401, successfully alleviated neuropathic pain in a Phase II clinical trial, the AT2R is receiving considerable attention as a new therapeutic target with human validation for the relief of peripheral neuropathic and chronic inflammatory pain conditions.
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Expert Opin. Ther. Targets · Sep 2014
Reviewβ-catenin as a regulator and therapeutic target for asthmatic airway remodeling.
Pathological alteration in the airway structure, termed as airway remodeling, is a hallmark feature of individuals with asthma and has been described to negatively impact lung function in asthmatics. Recent studies have raised considerable interest in the regulatory role of β-catenin in remodeling asthmatic airways. The WNT/β-catenin signaling pathway is the key to normal lung development and tightly coordinates the maintenance of tissue homeostasis under steady-state conditions. Several studies indicate the crucial role of β-catenin signaling in airway remodeling in asthma and suggest that this pathway may be activated by both the growth factors and mechanical stimuli such as bronchoconstriction. ⋯ The aberrant activation of β-catenin signaling by both WNT-dependent and -independent mechanisms in asthmatic airways plays a key role in remodeling the airways, including cell proliferation, differentiation, tissue repair and extracellular matrix production. These findings are interesting from both a mechanistic and therapeutic perspective, as several drug classes have now been described that target β-catenin signaling directly.
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Expert Opin. Ther. Targets · Aug 2014
Germline copy number variation in the YTHDC2 gene: does it have a role in finding a novel potential molecular target involved in pancreatic adenocarcinoma susceptibility?
The vast majority of pancreatic cancers occurs sporadically. The discovery of frequent variations in germline gene copy number can significantly influence the expression levels of genes that predispose to pancreatic adenocarcinoma. We prospectively investigated whether patients with sporadic pancreatic adenocarcinoma share specific gene copy number variations (CNVs) in their germline DNA. ⋯ Our results suggest that the YTHDC2 gene could be a potential candidate for pancreatic cancer susceptibility and a useful marker for early detection as well as for the development of possible new therapeutic strategies.
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Expert Opin. Ther. Targets · Jun 2013
ReviewTargeting erythropoietin for chronic neurodegenerative diseases.
Since erythropoietin (EPO) and EPO receptor (EPOR) are expressed in the central nervous system (CNS) beyond hematopoietic system, EPO illustrates a robust biological function in maintaining neuronal survival and regulating neurogenesis and may play a crucial role in neurodegenerative diseases. ⋯ Novel knowledge of the cell signaling pathways regulated by EPO in the CNS will allow us to establish the foundation for the development of therapeutic strategies against neurodegenerative diseases. Further investigation of the role of EPO in neurodegenerative diseases can not only formulate EPO as a therapeutic candidate, but also further identify novel therapeutic targets for these disorders.
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Expert Opin. Ther. Targets · Jun 2013
ReviewTransient receptor potential vanilloid 1 as a therapeutic target in analgesia.
The selective excitatory action of capsaicin followed by long-term chemoanalgesia due to an action on the 'capsaicin receptor' of C-polymodal nociceptors, cloned 15 years ago, opened up fascinating perspectives for a class of nociceptor blocking analgesics. ⋯ The unique 'multisteric' gating of TRPV1 channel which is opened and modulated in various conformational changes to natural stimuli differs from the operation of canonical ligand-gated channels and makes it suitable to initiate development of second generation of TRPV1 antagonists without on-target side effects of hyperthermia and risk of burn injury.