Rac3 is a small GTPase multifunctional protein that regulates cell adhesion, migration, and differentiation. It has been considered as an oncogene in breast cancer; however, its role in esophageal cancer and the regulation of its stability have not been studied. F-box proteins are major subunits within the Skp1-Cullin-1-F-box (SCF) E3 ubiquitin ligases that recognize particular substrates for ubiquitination and proteasomal degradation. Recently, we have shown that SCFFBXL19 targets Rac1 and RhoA, thus regulating Rac1 and RhoA ubiquitination and degradation. Here, we demonstrate the role of FBXL19 in the regulation of Rac3 site-specific ubiquitination and stability. Expression of TGFβ1 is associated with poor prognosis of esophageal cancer. TGFβ1 reduces tumor suppressor, E-cadherin, expression in various epithelial-derived cancers. Here we investigate the role of FBXL19-mediated Rac3 degradation in TGFβ1-induced E-cadherin down-regulation in esophageal cancer cells.

Ghrelin, a gastric hormone, exerts cardioprotective function by increasing myocardial contractility and vasodilation. Previous studies have reported that angiotensin II (Ang II) production increased in heart failure, which can induce cardiomyocyte apoptosis. In this study, we investigated the effect of ghrelin on Ang II–induced H9c2 cardiomyocyte apoptosis. The results showed that Ang II inhibited H9c2 cell viability, which was blocked by ghrelin. By annexin V–propidium iodide dual staining and 2′-deoxyuridine 5′-triphosphate nick end-labeling analysis, we found that Ang II induced H9c2 cell apoptosis, whereas coincubation of ghrelin with Ang II significantly reduced H9c2 cell apoptosis induced by Ang II. Simultaneously, the results revealed that ghrelin regulated the Ang II–induced imbalance of Bax and Bcl-2 expression and reduced Ang II–induced caspase-3 expression. Moreover, mRNA expressions of endoplasmic reticulum stress-related molecules GRP78, caspase-12, and C/EBP homologous protein were significantly upregulated by Ang II. However, their expressions were significantly inhibited by ghrelin. In addition, we found that ghrelin markedly inhibited Ang II–induced Ang II type 1 receptor expression. These data suggest that ghrelin may play an antagonistic role in Ang II–induced cardiomyocyte apoptosis via decreasing Ang II type 1 receptor expression and inhibiting the activation of endoplasmic reticulum stress pathway.

Transforming growth factor-beta1 (TGF-β1) is a major factor in pathogenesis of chronic hepatic injury. Carbon tetrachloride (CCl₄) is a liver toxicant, and CCl₄-induced liver injury in mouse is a classical animal model of chemical liver injury. However, it is still unclear whether TGF-β1 is involved in the process of CCl₄-induced acute chemical liver injury. The present study aimed to evaluate the role of TGF-β1 and its signaling molecule Smad3 in the acute liver injury induce by CCl₄. The results showed that CCl₄ induced acute liver injury in mice effectively confirmed by H&E staining of liver tissues, and levels of not only liver injury markers serum ALT and AST, but also serum TGF-β1 were elevated significantly in CCl₄-treated mice, compared with the control mice treated with olive oil. Our data further revealed that TGF-β1 levels in hepatic tissue homogenate increased significantly, and type II receptor of TGF-β (TβRII) and signaling molecules Smad2, 3, mRNA expressions and Smad3 and phospho-Smad3 protein levels also increased obviously in livers of CCl₄-treated mice. To clarify the effect of the elevated TGF-β1/Smad3 signaling on CCl₄-induced acute liver injury, Smad3 in mouse liver was overexpressed in vivo by tail vein injection of Smad3-expressing plasmids. Upon CCl₄ treatment, Smad3-overexpressing mice showed more severe liver injury identified by H&E staining of liver tissues and higher serum ALT and AST levels. Simultaneously, we found that Smad3-overexpressing mice treated with CCl₄ showed more macrophages and neutrophils infiltration in liver and inflammatory cytokines IL-1β and IL-6 levels increment in serum when compared with those in control mice treated with CCl₄. Moreover, the results showed that the apoptosis of hepatocytes increased significantly, and apoptosis-associated proteins Bax, cytochrome C and the cleaved caspase 3 expressions were up-regulated in CCl₄-treated Smad3-overexpressing mice as well. These results suggested that TGF-β1/Smad3 signaling was activated during CCl₄-induced acute liver injury in mice, and Smad3 overexpression aggravated acute liver injury by promoting inflammatory cells infiltration, inflammatory cytokines release and hepatocytes apoptosis. In conclusion, the activation of TGF-β signaling contributes to the CCl₄-induced acute liver injury. Thus, TGF-β1/Smad3 may serve as a potential target for acute liver injury therapy.

Activin A, a member of transforming growth factor β (TGF-β) superfamily, plays essential role in neuron survival as a neurotrophic and neuroprotective factor in central nervous system. However, the effects and mechanisms of activin A on the neurite outgrowth of dorsal root ganglia (DRG) remain unclear. In the present study, we found that activin A is expressed in DRG collected from chicken embryos on day 8 (E8). Moreover, activin A induced neurite outgrowth of the primary cultured DRG and maintained long-time survival of monolayer-cultured DRG neurons during the observation for 10 days. Follistatin (FS), an activin-binding protein, significantly inhibited activin A-induced neurite outgrowth of DRG, but fails to influence the effect of nerve growth factor (NGF) on DRG neurite outgrowth. Furthermore, the results showed that activin A significantly up-regulated mRNA expressions of activin receptor type IIA (ActRIIA) and calcitonin gene-related peptide (CGRP) in DRG, and stimulated serotonin (5-HT) production from DRG, indicating that activin A may induce DRG neurite outgrowth via promoting CGRP expression and stimulating 5-HT release. These data suggest that activin A plays an important role in the development of DRG by autocrine/paracrine manner.