Magnolol inhibited proliferation of human malignant melanoma A375-S2 cells. The drug induced oligonucleosomal fragmentation of DNA in A375-S2 cells and increased caspase-3, 8, 9 activities followed by the degradation of caspase-3 substrates, inhibitor of caspase dependent DNase (ICAD) and poly-(ADP-ribose) polymerase (PARP). Pan-caspase inhibitor (z-VADfmk), caspase-3 inhibitor (z-DEVD-fmk), capase-8 inhibitor (z-IETD-fmk), caspase-9 inhibitor (z-LEHD-fmk) and caspase-10 inhibitor (z-AEVD-fmk) inhibited magnolol-induced A375-S2 cell apoptosis. The level of anti-apoptotic mitochondrial protein Bcl-2 was up-regulated while the level of pro-apoptotic protein Bax was down-regulated. Taken together, our results indicate that magnolol induces apoptosis by activation of both mitochondrial and death receptor pathways in A375-S2 cells.

MicroRNAs (miRNAs) play critical roles in tumorigenesis and metastasis by negatively regulating gene expression through complementary binding to the 3'-untranslated region of target mRNAs. The role of miRNAs in expression of the tumor suppressor DAB2IP in bladder cancer (BC) remains unknown. The aim of the present study was to identify miRNAs targeting DAB2IP and determine their expression and function in BC. We predicted candidate miRNAs targeting DAB2IP using TargetScan software. Dual-luciferase reporter assays confirmed that miRNA-556-3p directly regulated DAB2IP expression. Quantitative RT-PCR and RNase protection assays showed that endogenous miRNA-556-3p expression was significantly upregulated in clinical samples of BC patients and BC cell lines and western blot analysis indicated that DAB2IP expression in BC tissues and BC cell lines was concurrently downregulated. Gain or loss of function studies showed that upregulation of miRNA-556-3p promoted proliferation, invasion, migration and colony formation of BC cells, whereas downregulation resulted in opposite effects. Importantly, restoration of DAB2IP expression rescued the effects induced by miRNA-556-3p. Overexpression of miRNA-556-3p in BC cells not only decreased DAB2IP expression, but also markedly increased Ras GTPase activity and ERK1/2 phosphorylation level. These findings suggest that DAB2IP is a direct target of miRNA-556-3p, and endogenous miRNA-556-3p expression shows inverse correlation with simultaneous DAB2IP expression in BC tissues and cells. miRNA-556-3p functions as a tumor promoter in tumorigenesis and metastasis of BC by targeting DAB2IP. Moreover, miRNA-556-3p-mediated DAB2IP suppression plays an oncogenic role by partial activation of the Ras-ERK pathway.

Familial hypercholesterolemia (FH) is an inherited disorder of blood lipid metabolism characterized by high serum low-density lipoprotein cholesterol levels and premature coronary artery disease. In this study, we used a system biology approach to identify co-expressed gene pairs that were potentially involved in the progression of FH and constructed a conserved co-expression network using these genes. A total of 4232 co-expressed relationships were identified and we verified the significance by random permutation. FH patients showed differences in lipoprotein and cholesterol metabolism in circulating monocytes and lymphocytes compared to healthy controls. We hope our study could aid in understanding of FH and could provide the basis for FH biomarker identification.

The left-right symmetric model (LRSM) is a well-motivated framework to restore parity and implement seesaw mechanisms for the tiny neutrino masses at or above the TeV-scale, and has a very rich phenomenology at both the high-energy and high-precision frontiers. In this paper we examine the phase transition and resultant gravitational waves (GWs) in the minimal version of LRSM. Taking into account all the theoretical and experimental constraints on LRSM, we identify the parameter regions with strong first-order phase transition and detectable GWs in the future experiments. It turns out in a sizeable region of the parameter space, GWs can be generated in the phase transition with the strength of 10−17 to 10−12 at the frequency of 0.1 to 10 Hz, which can be detected by BBO and DECIGO. Furthermore, GWs in the LRSM favor a relatively light SU(2)R-breaking scalar $$ {H}_3^0 $$ H 3 0 , which is largely complementary to the direct searches of a long-lived neutral scalar at the high-energy colliders. It is found that the other heavy scalars and the right-handed neutrinos in the LRSM also play an important part for GW signal production in the phase transition.