6E and 7C). Third, increased phosphorylation
of mothers against decapentaplegic homologs 2 and 3, which is downstream of TGF-β signaling, was observed in the spinal cords of SOD1mu mice,47 demonstrating that an activating SOD1 mutation leads to activation PI3K inhibitor of TGF-β signaling (Fig. 7C). The present study demonstrates the interaction between SOD1, NOX1, and NOX4 to generate ROS in HSCs and induce liver fibrosis. Building on the work of us6, 30, 32, 34, 42 and others,8, 35, 36, 48 this study establishes a role for Nox1 and Nox4 in generating oxidative damage to induce liver fibrosis. Treatment with GKT137831, a novel, first-in-class, specific Nox1/Nox4 inhibitor,17 reverses fibrogenic response by inhibiting ROS production and expression of fibrogenic genes in both WT and SOD1mut HSCs. Most important, GKT137831 blocks liver fibrosis and down-regulates markers Selleck EX527 of oxidative stress, inflammation,
and fibrosis in WT and SOD1mut mice. Taken together, these results indicate that dual inhibition of Nox1 and Nox4 might provide a unique opportunity for the treatment of liver fibrosis and other fibrotic diseases. Additional Supporting Information may be found in the online version of this article. “
“Background and Aim: Manometric studies on the human lower esophageal sphincter (LES) have shown radial asymmetry of the high-pressure zone (HPZ). The aim of this study was to compare the functional properties of human LES clasp and sling muscles, and to look at their relationship with the expression of muscarinic receptors
and intracellular Ca2+ concentration. Methods: Muscle strips of sling and clasp fibers from the LES were obtained from patients undergoing subtotal esophagectomy. Isometric tension responses of the strips to acetylcholine were studied. Western blotting and reverse transcription-polymerase chain reaction (RT-PCR) were used to determine the expression of five subtypes of muscarinic receptors. Intracellular Ca2+ ([Ca2+]i) was measured using laser scanning confocal microscopy. Results: Acetylcholine caused a concentration-dependent increase in the tension of sling and clasp strips, the sling Paclitaxel strip being stronger than clasp (P = 0.00). Messenger RNA and protein for the five muscarinic acetylcholine receptor (mAChRs) expressed in the sling and clasp muscles were highest for M2, and then in decreasing levels: M3 > M1 > M4 > M5. Acetylcholine caused significant elevation of [Ca2+]i in sling and clasp muscle cells in the presence of extracellular Ca2+ (1.5 mmol/L), and Ach-induced [Ca2+]i elevation was 1.6 times greater in sling cells than in clasp cells. Conclusion: Variation of intracellular concentrations of Ca2+ may be the reason for differential responses to acetylcholine for sling versus clasp fibers. However, these differences are not associated with the distribution and the level of expression of the five mAChRs between the two muscle types.