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1 It has been demonstrated that oxidized low-density lipoprotein (OX-LDL) is a risk factor in atherosclerosis by stimulating vascular smooth muscle cell (VSMC) proliferation. However, the mechanisms of OX-LDL-induced cell proliferation are not completely understood. Therefore, we investigated the e ect of OX-LDL on cell proliferation associated with mitogen-activated protein kinase (MAPK) activation in rat cultured VSMCs. 6 OX-LDL-induced [ 3 H]-thymidine incorporation and p42/p44 MAPK phosphorylation was inhibited by PD98059 (an inhibitor of MEK1/2) and SB203580 (an inhibitor of p38 MAPK) in a concentration-dependent manner. 7 Overexpression of dominant negative mutants of Ras (H-Ras-15A) and Raf (Raf-N4) signi®cantly suppressed MEK1/2 and p42/p44 MAPK activation induced by OX-LDL and PDGF-BB, indicating that Ras and Raf may be required for activation of these kinases. 8 These results suggest that the mitogenic e ect of OX-LDL is mediated through a PTX-sensitive G protein-coupled receptor that involves the activation of the Ras/Raf/MEK/MAPK pathway similar to that of PDGF-BB in rat cultured VSMCs.

The JAK2/STAT signaling pathway mediates cytokine receptor signals that are involved in cell growth, survival and homeostasis. JAK2 is a member of the Janus kinase (JAK) family and aberrant JAK2/STAT is involved with various diseases, making the pathway a therapeutic target. The similarity between the ATP binding site of protein kinases has made development of specific inhibitors difficult. Current JAK2 inhibitors are not selective and produce unwanted side effects. It is thought that increasing selectivity of kinase inhibitors may reduce the side effects seen with current treatment options. Thus, there is a great need for a selective JAK inhibitor. In this study, we identified a JAK2 specific inhibitor. We first identified key pharmacological interactions in the JAK2 binding site by analyzing known JAK2 inhibitors. Then, we performed structure-based virtual screening and filtered compounds based on their pharmacological interactions and identified compound NSC13626 as a potential JAK2 inhibitor. Results of enzymatic assays revealed that against a panel of kinases, compound NSC13626 is a JAK2 inhibitor and has high selectivity toward the JAK2 and JAK3 isozymes. Our cellular assays revealed that compound NSC13626 inhibits colorectal cancer cell (CRC) growth by downregulating phosphorylation of STAT3 and arresting the cell cycle in the S phase. Thus, we believe that compound NSC13626 has potential to be further optimized as a selective JAK2 drug.

The chemokines CXCL9 and CCL20 have been reported to be associated with ventricular dysfunction. This study was aimed to investigate the effects of CXCL9/CCL20 on cardiac fibrosis following myocardial infarction (MI). Blood samples of patients with MI were obtained to determine the serum CXCL9, CCL20, tumor necrosis factor-α (TNF-α), and transforming growth factor-β (TGF-β). The expression of CXCL9 and CCL20 in hypoxia-incubated H9c2 cells and TNF-α/TGF-β-activated peripheral blood mononuclear cells (PBMCs) were examined. The experimental MI of rats was produced by the intraperitoneal injection of isoproterenol (ISO) (85 mg/kg/day) for two consecutive days. The growth and migration of CXCL9/CCL20-incubated cardiac fibroblasts in vitro were evaluated. TNF-α/TGF-β-activated PBMCs showed an enhanced expression of CXCL9 and CCL20, while hypoxic H9c2 cells did not. Patients with MI had significantly enhanced levels of serum TGF-β and CXCL9 compared to healthy subjects. ISO-treated rats had increased serum CXCL9 levels and marked cardiac fibrosis compared to control rats. The trend of increased serum CCL20 in patients with MI and ISO-treated rats was not significant. CXCL9-incubated cardiac fibroblasts showed enhanced proliferation and migration. The findings of this study suggest that an enhanced expression of CXCL9 following MI might play a role in post-MI cardiac fibrosis by activating cardiac fibroblasts.

Propofol attenuates the muscarinic receptor-mediated airway muscle contraction. The mechanism underlying these effects was attenuation of inositol phosphate generation and inhibition of Ca2+ mobilization through the inhibition of the receptor-coupled signal-transduction pathway.