The death receptor ligand TRAIL is considered a promising candidate for cancer therapy because of its preferential toxicity to malignant cells. However its efficacy has been challenged by a number of resistance mechanisms. Therefore, agents that can overcome the resistance to enhance therapeutic efficacy of TRAIL are needed. In the current study, we found that bufalin, bufotalin and gamabufotalin, key members of bufadienolides isolated from a traditional Chinese medicine ChanSu, significantly potentiated human breast cancer cells with different status of ER-alpha to apoptosis induction of TRAIL, as evidenced by enhanced Annexin V/FITC positive cells (apoptotic cells), cytoplasmic histone-associated-DNA-fragments, membrane permeability transition (MPT), caspases activation and PARP cleavage. Further mechanistic investigation demonstrated that bufalin was able to significantly decrease Mcl-1 expression and modestly decrease Bcl-XL expression level. Down-regulations of these anti-apoptotic proteins were well correlated with inhibition of transcription factor STAT3 activation. The important consequence of down-regulation Mcl-1 in the enhancement action by combining bufalin with TRAIL was confirmed by either knockdown or overexpression of Mcl-1 approach. Our findings for the first time provided strong evidences that bufadienolide compounds have excellent potential to be developed as a novel class of sensitizers of TRAIL.

Terpecurcumins A-I (1-9), together with three known analogues (10-12), were isolated from the rhizomes of Curcuma longa (turmeric). They were derived from the hybridization of curcuminoids and bisabolanes. The structures and absolute configurations of 1-9 were elucidated on the basis of extensive spectroscopic data analysis, including NMR and electronic circular dichroism spectra. The configuration of 10 was further confirmed by X-ray crystallography. A plausible biogenetic relationship for 1-12 is proposed. Compounds 4, 6, 7, 10, and 11 showed higher cytotoxic activities (IC(50), 10.3-19.4 μM) than curcumin (IC(50), 31.3-49.2 μM) against human cancer cell lines (A549, HepG2, and MDA-MB-231).

Our previous study has shown that activation of JNK plays a critical role in Porcine reproductive and respiratory syndrome virus (PRRSV)-mediated apoptosis. In this follow-up study, we further investigated the mechanisms involved in modulation of PRRSV-mediated JNK activation and apoptosis. We found that unfolded protein response (UPR) was induced in response to PRRSV infection which in turn triggered JNK activation and apoptosis. We also found that p53 and Akt were activated at the early stage of infection and functioned as negative regulator of JNK activation to counteract the PRRSV-mediated apoptosis. Furthermore, induction of UPR, p53 and Akt was not only involved in modulation of PRRSV-mediated apoptosis, but also contributed to the virus replication. Our findings indicated that multiple signaling pathways were involved in modulation of PRRSV-mediated apoptosis of the host cells via regulating JNK signaling pathway and provided novel insights into understanding the mechanisms of pathogenesis of PRRSV infection.

(2013) Autophagy-dependent EIF2AK3 activation compromises ursolic acid-induced apoptosis through upregulation of MCL1 in MCF-7 human breast cancer cells, Autophagy, 9:2,[196][197][198][199][200][201][202][203][204][205][206][207]

As part of aetiological studies, we tested 28 samples collected from domestic geese showing enteritis and sporadic death. A novel group of avastroviruses was found in six samples. One isolate was completely sequenced, which comprised 7,148 nucleotides. Pairwise comparisons and phylogenetic analysis demonstrated that the goose astrovirus is highly divergent from all previously described avastroviruses. Our data support the view that domestic geese can be infected by astroviruses with different genetic backgrounds, and have raised a concern about the role of domestic geese as reservoirs for diverse astroviruses.