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Abstract: Agmatine, an endogenous ligand for imidazoline I1 receptor, has previously been shown to prevent opioid tolerance in rats and mice, but the cellular mechanisms remain unknown. In the present study, the effects of agmatine activation on imidazoline I1 receptor on the desensitization, down-regulation and internalization of μ opioid receptor were investigated. Two cell lines, CHO cells transfected μ opioid receptor (CHO-μ cells) and co-transfected μ opioid receptor and imidazoline I1 receptor antisera-selected protein (IRAS) (CHO-μ/IRAS cells), were used. In both CHO-μ cells and CHO-μ/IRAS cells, agmatine (0.01–10 μM) did not affect the desensitization of μ opioid receptor induced by [d-Ala2, N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) (10 μM) treatment for 30 min. However, agmatine (0.1–100 nM) co-pretreatment with DAMGO (1 μM) for 12 h concentration-dependently inhibited DAMGO-induced down-regulation of μ opioid receptor in CHO-μ/IRAS cells, but not in CHO-μ cells. Efaroxan, the I1/α2-adrenoceptors mix antagonist, completely reversed the inhibitory effect of agmatine, suggesting the participation of imidazoline I1 receptor. In addition, agmatine (1–100 nM) inhibited DAMGO-induced internalization of μ opioid receptor in CHO-μ/IRAS cells, which was reversed by efaroxan as well. While treatment with DAMGO (1 μM) or co-treatment with agmatine (1–100 nM) for 12 h failed to affect the mRNA level of μ opioid receptor. Taken together, these results indicate that the inhibitory effect of agmatine on tolerance in vitro might be related to attenuation of the internalization and down-regulation of μ opioid receptor via activation of imidazoline I1 receptor. [Copyright &y& Elsevier]

Abstract: In this study, we investigated the expression and function of thymosinα1 (Thyα1) in human pancreatic cancer. We found that human pancreatic cancer cell lines Panc-1, Panc03.27, ASPC-1, and PL45 cells significantly over-expressed the mRNA of Thyα1 as compared to the normal human pancreatic ductal epithelium (HPDE) cells.. Thyα1 mRNA and protein levels were also over-expressed in clinical pancreatic adenocarcinoma specimens. In addition, synthetic Thyα1 significantly promoted Panc-1 cell proliferation and increased phosphorylation of ERK1/2 and JNK. Furthermore, Thyα1 increased the secretion of multiple cytokines including IL-10, IL-13, and IL-17 in Panc-1 cells. Thus, Thyα1 may have a new role in pancreatic cancer pathogenesis. [Copyright &y& Elsevier]