Current pharmaceutical design
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Review
Disruption of Circadian Rhythms and Sleep in Critical Illness and its Impact on Innate Immunity.
The earth rotates on its axis around the sun, creating a day and night cycle, that caused the development of circadian rhythms. The circadian rhythm is primarily entrained by light, which is detected by the retina. Retinal ganglion cells project to a part of the hypothalamus termed suprachiasmatic nucleus. ⋯ In critically ill patients the circadian rhythm is substantially altered, supporting a dysfunctional innate immune response. This review discusses recent basic science findings on the interaction of the circadian rhythm and the innate immune system. Furthermore we give an outlook on potential future therapeutic strategies.
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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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The acid-sensing ion channel (ASIC) has emerged as a novel type of ion channel that is activated by extracellular protons as well as nonproton ligands. Advances in ASIC research have resolved its multifaceted structural and functional properties, including its widespread distribution, polymodal activation, and activity-dependent regulation of its expression. ⋯ Here we review the contribution of ASICs at the peripheral and central levels to the development of acute pain, inflammatory pain, neuropathic pain, and anxiety-related disorders, as well as their potential underlying mechanisms. Accumulating evidence suggests that ASICs represent a novel class of promising targets for developing effective therapies for pain and anxiety.
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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.