No abstract

Microcystin-LR (MC-LR) produced by cyanobacteria in diverse water systems is a potent specific hepatotoxin and has been documented to induce various liver diseases via oxidative stress. However, the underlying mechanisms are largely unknown. In the current study, we investigated the molecular events involved in the oxidative liver injury by MC-LR. Our results demonstrated that MC-LR induced liver injury in mice through a series of steps that began with the production of reactive oxygen species (ROS), which stimulated the sustained activation of JNK and its downstream targets, AP-1 and Bid. Furthermore, the mitochondrial proteomic analysis indicated that JNK activation affected some crucial enzymes of energy metabolism, led to mitochondria dysfunction, which contributed to hepatocyte apoptosis and oxidative liver injury by MC-LR. Our results reveal significant insights into the mechanisms of liver injury induced by microcystins, and serve as a framework for deciphering the role of JNK in oxidative stress-associated liver diseases.

The precise mechanisms underlying gender disparity in hepatocellular carcinoma (HCC) progression and prognosis are not understood. We demonstrate that oestrogen attenuates HCC progression in vitro and in vivo, and this may contribute to the gender differences in HCC behaviour. To investigate the role of oestrogen in HCC progression, we developed an orthotopic homograft tumour model by liver implantation of H22 cells. In combination with male castration, female ovariectomy, and oestrogen treatment, we tested the hypothesis that oestrogen contributes to gender disparity in this model. Pathological analyses were performed to examine the changes in biological behaviour of liver cancer cells, and two cell lines were used to investigate possible molecular mechanisms of the suppressive effect of oestrogen. Our data showed that oestrogen modulates HCC malignancy in vivo by reducing tumour cell invasion, arresting cell cycle progression, and promoting apoptosis, characterized by decreased expression of MMP-2, MMP-9, PCNA, cyclin A, cyclin D1, and Bcl-2, and increased expression in cleaved caspase 3. Through in vitro assays, we further confirmed the changes in expression levels of these related proteins, gained insights into the molecular cascades of oestrogen-induced HCC suppression, and indicated the oestrogen receptor α-mediated inhibition of NF-κB binding activity as a pivotal event in this process. This study represents a novel description of the mechanisms regarding the suppressive effects of oestrogen on HCC, adding a new understanding to the gender disparity in HCC progression. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

a b s t r a c tMitochondrial apoptotic pathway is precisely controlled by BCL-2 family. Complex interactions of BCL-2 family proteins constitute a bistable switch of which detailed experimental and theoretical delineation remains elusive. In this paper, combined approaches were used to explore the bistability of Bax activation switch. We found that Bax activation is indeed in an 'all-or-none' manner. The 'variable-delay, snap-action' nature for Bax activation is further explored theoretically. We suggest that bistability is largely attributed to topological structure and shows considerable robustness. Therefore, our study characterizes dynamics and sensitivities in intrinsic apoptotic pathway. Crown