American journal of translational research
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We recently proposed a role for the 2-pore-domain K(+) (K2P) channel TREK-1 in the regulation of cytokine release from alveolar epithelial cells (AECs) by demonstrating decreased IL-6 secretion from TREK-1 deficient cells, but the effects of altered TREK-1 expression on other inflammatory mediators remain poorly understood. We now examined the role of TREK-1 in TNF-α-induced MCP-1 release from human A549 cells. We hypothesized that TREK-1 regulates TNF-α-induced MCP-1 secretion via c-Jun N-terminal kinases (JNK)- and protein kinase-C (PKC)-dependent pathways. ⋯ Similarly, pharmacological inhibition of PKC decreased MCP-1 secretion from control and TREK-1 deficient cells, suggesting that alterations in JNK and PKC signaling pathways were unlikely the cause for the increased MCP-1 secretion from TREK-1 deficient cells. Furthermore, MCP-1 secretion from control and TREK-1 deficient cells was independent of extracellular Ca(2+) but sensitive to inhibition of intracellular Ca(2+) reuptake mechanisms. In summary, we report for the first time that TREK-1 deficiency in human AECs resulted in increased MCP-1 production and secretion, and this effect appeared unrelated to alterations in JNK-, PKC- or Ca(2+)-mediated signaling pathways in TREK-1 deficient cells.
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Early intervention using hypothermia treatment has been shown to reduce early inflammation, apoptosis and infarct size in animal models of cardiac ischemia/reperfusion. We have shown that 5'-adenosine monophosphate (5'-AMP) can induce a reversible deep hypothermia in mammals. We hypothesize that 5'-AMP-induced hypothermia (AIH) may reduce ischemic/reperfusion damage following myocardial infarct. ⋯ The overall infarct size of the heart was significantly smaller in AIH treated mice. Myocardial ischemia in mice given 5'-AMP without hypothermia had similar ischemia/reperfusion injuries as the euthermic control. Thus, the AIH cardio-protective effects were primarily hypothermia based.
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In eukaryotic cells, the endoplasmic reticulum (ER) is an organelle that is responsible for protein folding and assembly, lipid and sterol biosynthesis, and free calcium storage. In the past decade, intensive research effort has been focused on intracellular stress signaling pathways from the ER that lead to transcriptional and translational reprogramming of stressed cells. ⋯ Identifying the UPR components that are activated or suppressed in malignancy and exploring cancer therapeutic potentials by targeting the UPR are hot research spots. In this review, we summarize the recent progress in understating UPR signaling in cancer and its related therapeutic potential.
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14-3-3sigma is a member of a highly conserved family of 14-3-3 proteins that are present in all eukaryotic organisms. 14-3-3sigma has been considered as a tumor suppressor with reduced expression in some human cancers while its increased expression causes resistance to anticancer agents and radiation that cause DNA damages. The increased expression of 14-3-3sigma may also predict poor prognosis in some human cancers. Thus, 14-3-3sigma may play an important role as a double-edged sword in human cancers, which may attribute to its property as a molecular chaperone by binding to various protein ligands important to many cellular processes such as cell cycle checkpoint regulation and apoptosis in response to DNA damages. In this article, we will review recent studies and progresses in understanding 14-3-3sigma as a double-edged sword in human cancers.