Current pharmaceutical design
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Rheumatoid Arthritis (RA) is a chronic, inflammatory, autoimmune disease affecting diarthrodial joints and extra-articular tissues; in the absence of an effective treatment, it is characterized by persistent symmetrical and erosive synovitis which leads to structural joint damage and lifelong disability. Several autoantibodies have been associated with RA such as rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA). B cells have been shown to play a crucial role in the pathogenesis of RA by producing autoantibodies and promoting synovial inflammation through antigen presentation, T cells activation and cytokines production [1]. ⋯ Consequently, to date a "trial-and-error" approach is used in the prescription of biologics in RA, which has the obvious disadvantage of potentially exposing patients to drugs that they may not respond, with potential unnecessary side-effects, delaying use of an effective treatment and causing a significant economic burden to society. Therefore, identifying pre-treatment predictors of response with a customized stratification approach would be of invaluable importance in RA, also in consideration of the large number of biologics in development targeting novel pathways currently being tested in clinical trials. In this manuscript, we review existing data and provide future perspectives with regard to the role of synovial histopathology as a potential prognostic biomarker for patient stratification in RA, in particular regarding the use of specific biologic therapies.
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Long-term potentiation (LTP), referring to a lasting increase in efficacy of synaptic transmission, is a common mechanism of memory storage in central nervous system (CNS). LTP at C-fiber synapses in spinal dorsal horn is considered as a synaptic model of pathological pain, as the spinal LTP is only induced by noxious electrical and natural stimuli but not by innoxious ones and LTPinducible stimulation is capable of leading to lasting behavioral signs of pathological pain in human and in animals. The molecular mechanisms of spinal LTP at C-fiber synapses are similar to hippocampal LTP in following aspects. ⋯ Therefore, the drugs targeting at the above molecules may impair memory function of hippocampus. The striking difference between hippocampal LTP and spinal LTP at C-fiber synapses is that activation of glial cells and the over-expression of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin- beta (IL-1β), inhibit LTP in hippocampus, but promote LTP in spinal dorsal horn. The drugs targeting at the neuroinflammatory process may not only attenuate pathological pain but also improve memory in hippocampus.
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Atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia in adult population and confers significant thromboembolic risk. Endothelial dysfunction has been recognized as a possible contributor to thrombogenesis in AF. ⋯ Importantly, endothelial dysfunction has been documented in AF patients without cardio-pulmonary comorbidities or risk factors (so-called 'lone AF'), as well. In this review, we provide an overview of contemporary evidence for the alterations in endothelial function and endothelial injury in AF, with a focus on endothelial (dys)function in lone AF.
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Recent investigations of the cellular and molecular mechanisms of pain provide new hopes for more effective treatments for patients with chronic pain. At the molecular and genetic levels, new proteins and genes related to sensory sensation have been identified. ⋯ This disconnect between discovery and better treatment options is due, in part to the negative side effects associated with new treatment options, and also as a result of the ineffectiveness of these new drugs for inhibiting chronic pain. In this review, I will explore this disconnect between discovery and treatment, and propose that the failure of previous medicines can be due to their limited effects on injury-related plasticity, and question the common misperception of seeking compounds for high efficacy before understanding basic mechanisms of the target proteins in pain-related plasticity.