Expert opinion on therapeutic targets
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Expert Opin. Ther. Targets · Jan 2016
ReviewTherapeutic implications of innate immune system in acute pancreatitis.
Acute pancreatitis (AP) is an inflammatory disorder of the pancreas encompassing a cascade of cellular and molecular events. It starts from premature activation of zymogens with the involvement of innate immune system to a potential systemic inflammatory response and multiple organ failure. Leukocytes are the major cell population that participate in the propagation of the disease. Current understanding of the course of AP is still far from complete, limiting treatment options mostly to conservative supportive care. Emerging evidence has pointed to modulation of the immune system for strategic therapeutic development, by mitigating the inflammatory response and severity of AP. In the current review, we have focused on the role of innate immunity in the condition and highlighted therapeutics targeting it for treatment of this challenging disease. ⋯ The current state of knowledge on AP, limitations of presently available therapeutic approaches and the promise of therapeutic implications of innate immune system in AP are discussed.
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Kisspeptins are a family of neuropeptides whose identification has become one of the biggest discoveries in reproductive endocrinology during the past decade. Kisspeptins act upstream of GnRH as high-level mediators of the reproductive axis. ⋯ The identification of the kisspeptin signaling pathway has greatly advanced the study of reproductive endocrinology. Building on a large body of animal data, a growing number of human studies have shown that exogenous kisspeptin can stimulate physiological gonadotropin responses in both healthy subjects and those with disorders of reproduction. There is an increasing appreciation that kisspeptin may act as a signal transmitter between metabolic status and reproductive function. Future work is likely to involve investigation of novel kisspeptin analogs and further exploration of role of neurokinin B and dynorphin on the kisspeptin-GnRH axis.
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Expert Opin. Ther. Targets · Apr 2015
ReviewBrain-derived neurotrophic factor as a driving force behind neuroplasticity in neuropathic and central sensitization pain: a new therapeutic target?
Central sensitization is a form of maladaptive neuroplasticity underlying many chronic pain disorders, including neuropathic pain, fibromyalgia, whiplash, headache, chronic pelvic pain syndrome and some forms of osteoarthritis, low back pain, epicondylitis, shoulder pain and cancer pain. Brain-derived neurotrophic factor (BDNF) is a driving force behind neuroplasticity, and it is therefore crucial for neural maintenance and repair. However, BDNF also contributes to sensitization of pain pathways, making it an interesting novel therapeutic target. ⋯ This section focuses on combining pharmacotherapy with multimodal rehabilitation for balancing the deleterious and therapeutic effects of BNDF treatment in chronic pain patients, as well as accounting for the complex and biopsychosocial nature of chronic pain.
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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.