British journal of pharmacology
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Infection with Gram-negative bacteria has been recognized as an initiator of rheumatoid arthritis, which is characterized by chronic inflammation and infiltration of immune cells. Carbon monoxide (CO) exhibits anti-inflammatory properties. Here we have investigated the detailed mechanisms of vascular cell adhesion molecule-1 (VCAM-1) expression induced by LPS and if CO inhibited LPS-induced leukocyte adhesion to synovial fibroblasts by suppressing VCAM-1 expression. ⋯ LPS-mediated formation of the TLR4/MyD88/TRAF6/c-Src complex regulated NF-κB and MAPKs/AP-1 activation leading to VCAM-1 expression and leukocyte adhesion. CORM-2, which liberates CO to elicit direct biological activities, attenuated LPS-induced VCAM-1 expression by interfering with NF-κB and AP-1 activation, and significantly reduced LPS-induced immune cell infiltration of the synovium.
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A growing number of studies have demonstrated that oxytocin (OT) plays an analgesic role in modulation of nociception and pain. Most work to date has focused on the central mechanisms of OT analgesia, but little is known about whether peripheral mechanisms are also involved. Acid-sensing ion channels (ASICs) are distributed in peripheral sensory neurons and participate in nociception. Here, we investigated the effects of OT on the activity of ASICs in dorsal root ganglion (DRG) neurons. ⋯ These results reveal a novel peripheral mechanism for the analgesic effect of OT involving the modulation of native ASICs in primary sensory neurons mediated by V1A receptors.
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Transient receptor potential-3 (TRPM3) channels function as Ca2+ permeable cation channels. While the natural ligands for these channels are still unknown, several compounds have been described that either activate or inhibit TRPM3 channel activity. experimental approach: We assessed TRPM3-mediated gene transcription, which relies on the induction of intracellular signalling to the nucleus following activation of TRPM3 channels. Activator protein-1 (AP-1) and Egr-1-responsive reporter genes were integrated into the chromatin of the cells. This strategy enabled us to analyse gene transcription of the AP-1 and Egr-1-responsive reporter genes that were packed into an ordered chromatin structure. ⋯ Pregnenolone sulfate is a powerful activator of TRPM3-mediated gene transcription, while transcription is completely inhibited by mefenamic acid in cells expressing activated TRPM3 channels. Both compounds are valuable tools for further investigating the biological functions of TRPM3 channels.
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An intracellular redox sensor for reactive oxygen species at the M3-M4 linker of GABAA ρ1 receptors.
Reactive oxygen species (ROS) are normally involved in cell oxidative stress but also play a role as cellular messengers in redox signalling; for example, modulating the activity of neurotransmitter receptors and ion channels. However, the direct actions of ROS on GABAA receptors were not previously demonstrated. In the present work, we studied the effects of ROS on GABAA ρ1 receptor function. ⋯ Our results show that the function of GABAA ρ1 receptors is enhanced by ROS and that the intracellular C³⁶⁴ is the sensor for ROS actions.
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Aleglitazar is a dual PPARα/γ agonist but little is known about its effects on vascular function and atherogenesis. Hence, we characterized its effects on circulating angiogenic cells (CAC), neoangiogenesis, endothelial function, arteriogenesis and atherosclerosis in mice. ⋯ Aleglitazar augments the number, function and survival of CAC, which correlates with improved vascular function, enhanced arteriogenesis and prevention of atherosclerosis in mice.