5 ± 4.0 ng/mg versus vehicle 30.7 ± 4.8 ng/mg, P < 0.01). KU-57788 solubility dmso Further, we noted a consistent increase of HGF levels at

120 hours after hepatectomy in the mice receiving continuous sorafenib treatment and the mice starting sorafenib after surgery, although this was not significant. At the time of sacrifice, the abdominal scar was excised and the suture removed carefully. Although the scar margins of the control animals remained sealed, mice receiving sorafenib until harvest had more fragile scars, i.e., the margins were not sealed or separated in a zip-like fashion upon minimal traction. Histological analysis of scar tissue revealed differences in the scar of vehicle- and sorafenib-treated animals. The scars of vehicle control animals presented tissue remodeling of the muscular wall with dense granulation tissue filling the wound cleft (Fig. 6, top panel). Quantification of bridging reactions revealed no significant differences 72 hours after surgery. selleck screening library However, at

120 hours we observed significantly less bridges in animals that had received sorafenib treatment after surgery compared to vehicle controls (120 hours, continuous sorafenib 1.8 ± 1.1 versus vehicle 4.2 ± 1.8, P < 0.05; sorafenib postsurgery 1.8 ± 1.4 versus vehicle 4.2 ± 1.8, P < 0.01) (Fig. 7). Moreover, the scars of animals that were treated with sorafenib after surgery showed less intense tissue remodeling and granulation tissue was less dense or barely present (Fig. 6, lower panels). Our preclinical results show that sorafenib administration that is stopped 1 day before hepatic resection had no effect on liver regeneration in this study, whereas liver regeneration was impaired at the late timepoint examined (120 hours) when sorafenib was administered

postoperatively. Liver regeneration is a complex process that depends on the activation of several growth signal pathways. Sorafenib inhibits the serine/threonine kinase activity of RAF in the RAF/MEK/ERK signaling pathway and the receptor tyrosine kinase activity of the VEGF receptor-2.9 Liver regeneration studies have shown that a variety of growth factors and cytokines, acting by way of their respective receptors, activate complementary signaling pathways that elicit cellular proliferation and liver mass restoration. Among these intracellular mediator 上海皓元医药股份有限公司 is the RAS/RAF/MEK pathway, resulting in the activation of ERK1/2.12 Growth factors such as EGF, HGF, and TGFα and different cytokines (interleukin-6 [IL-6], TNF [tumor necrosis factor]) trigger ERK1/2 activation.16-18 This mitogenic cascade is inhibited by sorafenib at the level of RAF. Our analysis of phosphorylated ERK by immunohistochemistry showed decreased levels in the sorafenib-treated animals, with an important inhibition of ERK activation after hepatectomy but also diminished baseline phospho-ERK contents at the time of hepatectomy in the animals that had received sorafenib treatment prior to surgery.