49 research outputs found
Economics of the US - Canada Softwood Lumber Dispute: A Historical Perspective
No full textThis paper reviews the U.S.-Canada softwood lumber dispute over the past two decades by outlining the key developments and critically appraising the arguments put forward by both countries. It also presents a welfare analysis of lumber trade distortions. Given the importance of lumber trade between Canada and the United States, an expeditious resolution of this long-running trade dispute would be beneficial for both countries.antidumping and countervailing duties, lumber, trade distortions, welfare, Resource /Energy Economics and Policy,
Phosphorylation of the norepinephrine transporter at threonine 258 and serine 259 is linked to protein kinase C-mediated transporter internalization
No full textRecently, we have demonstrated the phosphorylation- and lipid raft-mediated internalization of the native norepinephrine transporter (NET) following protein kinase C (PKC) activation (Jayanthi, L. D., Samuvel, D. J., and Ramamoorthy, S. (2004) J. Biol. Chem. 279, 19315-19326). Here we tested an hypothesis that PKC-mediated phosphorylation of NET is required for transporter internalization. Phosphoamino acid analysis of 32P-labeled native NETs from rat placental trophoblasts and heterologously expressed wild type human NET (WT-hNET) from human placental trophoblast cells revealed that the phorbol ester (beta-PMA)-induced phosphorylation of NET occurs on serine and threonine residues. Beta-PMA treatment inhibited NE transport, reduced plasma membrane hNET levels, and stimulated hNET phosphorylation in human placental trophoblast cells expressing the WT-hNET. Substance P-mediated activation of the G alpha(q)-coupled human neurokinin 1 (hNK-1) receptor coexpressed with the WT-hNET produced effects similar to beta-PMA via PKC stimulation. In striking contrast, an hNET double mutant harboring T258A and S259A failed to show NE uptake inhibition and plasma membrane redistribution by beta-PMA or SP. Most interestingly, the plasma membrane insertion of the WT-hNET and hNET double mutant were not affected by beta-PMA. Although the WT-hNET showed increased endocytosis and redistribution from caveolin-rich plasma membrane domains following beta-PMA treatment, the hNET double mutant was completely resistant to these PKC-mediated effects. In addition, the PKC-induced phosphorylation of hNET double mutant was significantly reduced. In the absence of T258A and S259A mutations, alanine substitution of all other potential phosphosites within the hNET did not block PKC-induced phosphorylation and down-regulation. These results suggest that Thr-258 and Ser-259 serve as a PKC-specific phospho-acceptor site and that phosphorylation of this motif is linked to PKC-induced NET internalization
LP340, a novel histone deacetylase inhibitor, decreases liver injury and fibrosis in mice: role of oxidative stress and microRNA-23a
No full textEffective therapy for liver fibrosis is lacking. Here, we examined whether LP340, the lead candidate of a new-generation of hydrazide-based HDAC1,2,3 inhibitors (HDACi), decreases liver fibrosis. Liver fibrosis was induced by CCl4 treatment and bile duct ligation (BDL) in mice. At 6 weeks after CCl4, serum alanine aminotransferase increased, and necrotic cell death and leukocyte infiltration occurred in the liver. Tumor necrosis factor-α and myeloperoxidase markedly increased, indicating inflammation. After 6 weeks, α-smooth muscle actin (αSMA) and collagen-1 expression increased by 80% and 575%, respectively, indicating hepatic stellate cell (HSC) activation and fibrogenesis. Fibrosis detected by trichrome and Sirius-red staining occurred primarily in pericentral regions with some bridging fibrosis in liver sections. 4-Hydroxynonenal adducts (indicator of oxidative stress), profibrotic cytokine transforming growth factor-β (TGFβ), and TGFβ downstream signaling molecules phospho-Smad2/3 also markedly increased. LP340 attenuated indices of liver injury, inflammation, and fibrosis markedly. Moreover, Ski-related novel protein-N (SnoN), an endogenous inhibitor of TGFβ signaling, decreased, whereas SnoN expression suppressor microRNA-23a (miR23a) increased markedly. LP340 (0.05 mg/kg, ig., daily during the last 2 weeks of CCl4 treatment) decreased 4-hydroxynonenal adducts and miR23a production, blunted SnoN decreases, and inhibited the TGFβ/Smad signaling. By contrast, LP340 had no effect on matrix metalloproteinase-9 expression. LP340 increased histone-3 acetylation but not tubulin acetylation, indicating that LP340 inhibited Class-I but not Class-II HDAC in vivo. After BDL, focal necrosis, inflammation, ductular reactions, and portal and bridging fibrosis occurred at 2 weeks, and αSMA and collagen-1 expression increased by 256% and 560%, respectively. LP340 attenuated liver injury, ductular reactions, inflammation, and liver fibrosis. LP340 also decreased 4-hydroxynonenal adducts and miR23a production, prevented SnoN decreases, and inhibited the TGFβ/Smad signaling after BDL. In vitro, LP340 inhibited immortal human hepatic stellate cells (hTERT-HSC) activation in culture (αSMA and collagen-1 expression) as well as miR23a production, demonstrating its direct inhibitory effects on HSC. In conclusions, LP340 is a promising therapy for both portal and pericentral liver fibrosis, and it works by inhibiting oxidative stress and decreasing miR23a
Lactate Boosts TLR4 Signaling and NFκB Pathway-Mediated Gene Transcription in Macrophages via Monocarboxylate Transporters and MD-2 Upregulation
No full texthttps://medica-musc.researchcommons.org/posters/1002/thumbnail.jp
Ouabain–Induced Auditory Nerve Degeneration in Congenic Ly5.1 Mice
No full textAbstractThe Ly5.1 mouse, also termed B6.SJL–PtprcaPepcb/BoyJ, is a congenic strain widely used as a recipient in animal studies of bone marrow transplant. Our previous study documented that a majority of type I spiral ganglion neurons (SGNs) in the apical turns of Ly5.1 mice are unmyelinated and aggregate into neuronal clusters, similar to the spiral ganglion in the human ear. Ouabain, a well known Na–K ATPase inhibitor, has been shown to induce neuronal degeneration in a variety of neural tissues including the adult gerbil and CBA/CaJ mouse spiral ganglion. Here, functional and pathological changes of the auditory nerves in young–adult Ly5.1 mice were examined at 3, 7 and 14 days after ouabain exposure. Similar to observations in CBA/CaJ mice, ouabain application selectively removed type I SGNs, resulting in an immense decline of the auditory nerve function. Hyperplasia of glial cells was seen in the injured auditory nerves at 7 days after ouabain exposure. Our data indicate that the “human–like” features of unmyelinated type I SGNs have no protective impact on the fate of SGNs after ouabain exposure. Cells incorporating bromodeoxyuridine (BrdU) and expressing Sox2 were also counted in the auditory nerves of control and ouabain–treated ears. The number of Sox2+glial cells significantly increased at 3 and 7 days post–treatment. Interestingly, the highest density of BrdU+ cells appeared in the apical turn of the injured auditory nerve shortly after ouabain exposure, suggesting that the pattern of SGN loss at the apical turn in Ly5.1 mouse may have some impact on the reaction of non–neuronal cells in response to acute ototoxic drug exposure in the auditory nerve
Combination therapy of lovastatin and AMP-activated protein kinase activator improves mitochondrial and peroxisomal functions and clinical disease in experimental autoimmune encephalomyelitis model
No full textCrosstalk between Adipocytes and Mononuclear Cells Stimulates Osteopontin Expression via IL-6 and IL-1β
No full texthttps://medica-musc.researchcommons.org/posters/1009/thumbnail.jp
High Glucose and Interleukin 6 Synergistically Stimulate Matrix Metalloproteinase-1 Expression by U937 Mononuclear Cells through c-Jun Upregulation and ERK and JNK Cascades
No full texthttps://medica-musc.researchcommons.org/posters/1005/thumbnail.jp
GABA Transmission in the Nucleus Accumbens Is Altered after Withdrawal from Repeated Cocaine
No full textSimvastatin suppresses LPS-induced MMP-1 expression in U937 mononuclear cells by inhibiting protein isoprenylation-mediated ERK activation
No full texthttps://medica-musc.researchcommons.org/posters/1004/thumbnail.jp
