We investigated the molecular mechanisms underlying the effect of sorafenib and SC-59, a novel sorafenib derivative, on hepatocellular carcinoma (HCC). Sorafenib activated autophagy in a dose- and time-dependent manner in the HCC cell lines PLC5, Sk-Hep1, HepG2 and Hep3B. Sorafenib downregulated phospho-STAT3 (P-STAT3) and subsequently reduced the expression of myeloid cell leukemia-1 (Mcl-1). Inhibition of Mcl-1 by sorafenib resulted in disruption of the Beclin 1-Mcl-1 complex; however, sorafenib did not affect the amount of Beclin 1, suggesting that sorafenib treatment released Beclin 1 from binding with Mcl-1. Silencing of SHP-1 by small interference RNA (siRNA) reduced the effect of sorafenib on P-STAT3 and autophagy. Ectopic expression of Mcl-1 abolished the effect of sorafenib on autophagy. Knockdown of Beclin 1 by siRNA protected the cells from sorafenib-induced autophagy. Moreover, SC-59, a sorafenib derivative, had a more potent effect on cancer cell viability than sorafenib. SC-59 downregulated P-STAT3 and induced autophagy in all tested HCC cell lines. Furthermore, our in vivo data showed that both sorafenib and SC-59 inhibited tumor growth, downregulated P-STAT3, enhanced the activity of SHP-1 and induced autophagy in PLC5 tumors, suggesting that sorafenib and SC-59 activate autophagy in HCC. In conclusion, sorafenib and SC-59 induce autophagy in HCC through a SHP-1-STAT3-Mcl-1-Beclin 1 pathway.

Two trials were conducted to study the effects of two Chinese herbal polysaccharides [achyranthan (ACH), a low-molecular-weight polysaccharide, and astragalan (APS), a high-molecular-weight polysaccaride] on the immunity and growth performance of young broilers. Trial 1 was a 28-d growth assay, in which 7-d-old broilers (n = 240) were randomly allotted to one of three dietary treatments, with eight replicate pens per treatment and ten chickens per pen. Dietary treatments included a control corn-soy-fishmeal (Treatment 1), a diet with 200 mg/kg APS (Treatment 2), and a diet with 200 mg/kg ACH (Treatment 3). Blood samples were collected by cardiac puncture on Days 7, 14, 21, and 28 for determination of serum parameters, and chickens were killed on Day 28 to measure immune organ indexes. Trial 2 was an in vitro trial to study the effects of different concentrations of polysaccharides on broiler splenocyte functions. In Trial 1, feeding either APS or ACH had no significant effects on growth performance of broilers relative to the control. However, compared to the control, feeding ACH significantly increased microhemagglutination inhibition (HI) antibody titers, bursa of Fabricius index, serum albumin, serum calcium, and nitric oxide (NO) concentrations at Day 28 (P < or = 0.05). In Trial 2, both polysaccharides showed significant immunostimulating effects. They increased NO and interleukin-2 (IL-2) production of splenocytes and enhanced splenocyte proliferation in a dose-dependent manner (P < 0.05). Those results indicate that the immunostimulating effects of APS are not as pronounced as those of ACH. Achyranthan showed immunostimulating effects in both the growth assay and in vitro studies. Therefore, ACH may be a Chinese herbal polysaccharide that has the potential to be used as a feed additive to improve broilers' immunity.

Xanthine dehydrogenase (XDH), a rate-limiting enzyme involved in purine metabolism, has an essential role in inflammatory cascades. Researchers have known for decades that XDH activity is decreased in some cancers, including hepatocellular carcinoma (HCC). However, the role of XDH in cancer pathogenesis has not been fully explored. In this study, we showed that low XDH mRNA levels were correlated with higher tumor stages and poorer prognoses in patients with HCC. Knocking down or inhibiting XDH promoted migration and invasion but not proliferation of HCC cells. The abovementioned phenotypic changes are dependent on increases in epithelial-mesenchymal transition marker gene expression and transforming growth factor-β-Smad2/3 signaling activity in HCC. XDH overexpression suppressed HCC cell invasion in vitro and in vivo. In addition, the expression and activity of XDH were associated with the expression of CSC-related genes, such as CD44 or CD133, in HCC cells. These data suggest that downregulated XDH expression may be a useful clinical indicator and contribute to the development and progression of HCC.