First, we review preclinical data supporting the serotonergic raphe nuclei and their forebrain projections as targets of drugs of abuse, with emphasis on the effects of psychostimulants, opioids and ethanol. Next, we examine the role of 5-HT receptors in impulsivity, a core behavior that contributes to the vulnerability to addiction and relapse. Finally, we discuss evidence for serotonergic dysregulation in comorbid mood and addictive disorders and suggest novel serotonergic targets for the treatment of addiction and the prevention of drug relapse.
This article is part of a Special Issue entitled GANT61 purchase ‘Serotonin: The New Wave’. (C) 2011 Elsevier Ltd. All rights reserved.”
“Objective:
Obliterative bronchiolitis is
the predominant histopathologic finding in patients with chronic rejection after lung transplant. see more This fibroproliferative transformation within small airways of lung allograft is poorly understood; however, studies suggest epithelial-mesenchymal transition plays a role. Transplant immunosuppressive therapy has been shown to cause epithelial-mesenchymal transition in renal tubular epithelial cells, with subsequent fibrosis. This study explored whether immunosuppressive therapy contributes to epithelial-mesenchymal transition in airway epithelial cells.
Methods: Bronchial epithelial cell line RL-65 was treated 3 to 5 days with several immunosuppressive agents, including cyclosporine (INN ciclosporin), tacrolimus, azathioprine, mycophenolic acid, sirolimus, prednisone, and transforming growth factor beta
1 as control. We then analyzed cells for presence of mesenchymal morphology and protein markers.
Results: Treatment with cyclosporine, azathioprine, mycophenolate, and sirolimus resulted in elongated and irregular cell shape, and all but azathioprine showed loss of cell-cell adhesions relative to vehicle-treated cells. Expressions of extracellular matrix proteins, fibronectin and collagen, along with mesenchymal marker, vimentin, were significantly upregulated. Immunofluorescence showed loss of E-cadherin at cell membranes and cytoskeletal Bay 11-7085 rearrangements typical of epithelial-mesenchymal transition. These immunosuppressive agents also increased transforming growth factor produced by cells; however, tacrolimus-and prednisone-treated cells maintained epithelial morphology, baseline levels of matrix protein expression, and transforming growth factor production levels.
Conclusions: Overall, we found that certain immunosuppressive agents may contribute to partial epithelial-mesenchymal transition in bronchial epithelial cells, specifically increasing production of excessive extracellular matrix proteins. This may provide novel insights into the pathogenesis of obliterative bronchiolitis after lung transplant.