American journal of physiology. Cell physiology
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Am. J. Physiol., Cell Physiol. · Nov 2009
Cholinergic agonists regulate JAK2/STAT3 signaling to suppress endothelial cell activation.
The cholinergic anti-inflammatory pathway is a physiological mechanism that inhibits cytokine production and minimizes tissue injury during inflammation. Previous investigations revealed that cholinergic stimulation (via cholinergic agonists and vagus nerve stimulation) suppresses endothelial cell activation and leukocyte recruitment. The purpose of this study was to investigate the mechanisms by which cholinergic agonists (e.g., nicotine and GTS-21) regulate endothelial cell activation. ⋯ Finally, we observed that nicotine and GTS-21 treatment decreased levels of SOCS3 (suppressor of cytokine signaling; a regulator of the inflammatory activity of IL-6) in activated endothelial cells. These data demonstrate that cholinergic agonists suppress IL-6-mediated endothelial cell activation through the JAK2/STAT3 pathway. Our results have significant implications for better understanding the therapeutic potential of cholinergic agonists for treating IL-6 mediated inflammatory conditions.
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During brain trauma, white matter experiences shear and stretch forces that, without severing axons, nevertheless trigger their secondary degeneration. In central nervous system (CNS) trauma models, voltage-gated sodium channel (Nav) blockers are neuroprotective. This, plus the rapid tetrodotoxin-sensitive Ca2+ overload of stretch-traumatized axons, points to "leaky" Nav channels as a pivotal early lesion in brain trauma. ⋯ Nav1.6 channel responses to cell and membrane trauma are therefore consistent with the hypothesis that mechanically induced Nav channel leak is a primary lesion in traumatic brain injury. Nav1.6 is the CNS node of Ranvier Nav isoform. When, during head trauma, nodes experienced bleb-inducing membrane damage of varying intensities, nodal Nav1.6 channels should immediately "leak" over a broadly left-smeared window current range.
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Am. J. Physiol., Cell Physiol. · Sep 2009
17Beta-estradiol restores excitability of a sexually dimorphic subset of myelinated vagal afferents in ovariectomized rats.
We recently identified a myelinated vagal afferent subpopulation (Ah type) far more prevalent in female than male rats and showed that this difference extends to functionally specific visceral sensory afferents, baroreceptors of the aortic arch. Excitability of myelinated Ah-type afferents is markedly reduced after ovariectomy (OVX). Here we tested the hypothesis that 17beta-estradiol can selectively restore excitability of these sex-specific vagal afferents. ⋯ These data support our conclusions that the cellular mechanisms leading to rapid restoration of neuronal excitability of myelinated Ah-type VGN after OVX occur, at least in part, via membrane-bound estrogen receptors. We contend that recovery of high-frequency discharge at physiologically relevant 17beta-estradiol concentrations implies that this unique subtype of low-threshold myelinated vagal afferent may account for some of the sex-related differences in visceral organ system function. Sex differences in cardiovascular and gastrointestinal function and the potential role of GPR30 in modulation of sex-specific myelinated Ah-type vagal afferents are discussed.
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Interleukin-1 (IL-1) is an inflammatory cytokine that has been linked to muscle catabolism, a process regulated by muscle-specific E3 proteins of the ubiquitin-proteasome pathway. To address cellular mechanism, we tested the hypothesis that IL-1 induces myofibrillar protein loss by acting directly on muscle to increase expression of two critical E3 proteins, atrogin1/muscle atrophy F-box (MAFbx) and muscle RING-finger 1 (MuRF1). Experiments were conducted using mature C2C12 myotubes to eliminate systemic cytokine effects and avoid paracrine signaling by nonmuscle cell types. ⋯ Other regulators of E3 expression are unaffected by IL-1 [cytosolic oxidant activity, Forkhead-O (Foxo) activity] or respond paradoxically (AKT). Chronic exposure of C2C12 myotubes over 48 h resulted in reduced myotube width and loss of sarcomeric actin. We conclude that IL-1alpha and IL-1beta act via an oxidant- and AKT/Foxo-independent mechanism to activate p38 MAPK, stimulate NF-kappaB signaling, increase expression of atrogin1/MAFbx and MuRF1, and reduce myofibrillar protein in differentiated myotubes.
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Am. J. Physiol., Cell Physiol. · Aug 2009
CommentPseudomonas aeruginosa: can studies in engineered cells tell us why is it such a problem in people with cystic fibrosis? Focus on "Cystic fibrosis transmembrane conductance regulator and caveolin-1 regulate epithelial cell internalization of Pseudomonas aeruginosa".