Hepatitis B virus (HBV) causes chronic hepatitis in hundreds of millions of people worldwide, which can eventually lead to hepatocellular carcinoma (HCC). The molecular mechanisms underlying HBV persistence are not well understood. TRAIL, the TNF-related apoptosis-inducing ligand, has recently been implicated in hepatocyte death during HBV infection. We report here that the HBV core protein (HBc) is a potent inhibitor of TRAIL-induced apoptosis. Overexpressing HBc significantly decreased TRAIL-induced apoptosis of human hepatoma cells, whereas knocking-down HBc expression in hepatoma cells transfected with HBV genome enhanced it. When present in the same cell, HBc blocked the pro-apoptotic effect of the HBV X protein (HBx). The resistance of HBc-expressing cells to TRAIL-induced apoptosis was associated with a significant reduction in death receptor 5 (DR5) expression. Upon transfection, HBc significantly repressed the promoter activity of the human DR5 gene. Importantly, HBc gene transfer inhibited hepatocyte death in a mouse model of HBV-induced hepatitis; and in patients with chronic hepatitis, DR5 expression in the liver was significantly reduced. These results indicate that HBc may prevent hepatocytes from TRAIL-induced apoptosis by blocking DR5 expression, which in turn contributes to the development of chronic hepatitis and HCC. They also call into question the potential side effects of HBc-based vaccines. Hepatitis B virus (HBV) infection remains to be a major health problem worldwide despite the availability of an effective vaccine. More than 350 million people are chronically infected with HBV who are at a high risk of developing hepatitis, cirrhosis and hepatocellular carcinoma. 1 To date, the molecular mechanisms of chronic HBV infection have not been elucidated in detail. Recent studies suggest that resistance of HBV-infected hepatocytes to apoptosis may contribute to the development of chronic hepatitis. 2 Apoptosis of hepatocytes during HBV infection is mediated by several molecular pathways, which involve at least three members of the TNF superfamily, that is, TNF, Fas ligand (FasL) and TRAIL. Unlike TNF and FasL, TRAIL preferentially induces apoptosis of tumor cells and virus-infected cells but not normal cells. [3][4][5] Blocking the TRAIL pathway using soluble death receptor 5 (DR5) significantly ameliorates liver inflammation in a mouse model of hepatitis B. 6 Interestingly, two HBV proteins, HBV X (HBx) 5 and truncated middle hepatitis B surface protein (MHBs(t)), 7 were recently found to sensitize hepatocytes to TRAIL-induced apoptosis.The TRAIL apoptotic pathway is strictly controlled at both the receptor and intracellular signaling levels. Five receptors for TRAIL have been identified, including two death receptors (DR4 and DR5, also known as TRAIL-R1 and TRAIL-R2, respectively) and two decoy receptors (decoy receptor 1(DcR1, TRAIL-R3, and TRID) and decoy receptor 2 (DcR2, TRAIL-R4, and TRUNDD)). 4,8,9 In mice, only one membrane TRAIL receptor has been identified, which shares 79% sequenc...

We previously reported that marchantin M (Mar) is an active agent to induce apoptosis in human prostate cancer (PCa), but the molecular mechanisms of action remain largely unknown. Here, we demonstrate that Mar potently inhibited chymotrypsin-like and peptidyl-glutamyl peptide-hydrolyzing activities of 20S proteasome both in in vitro and intracellular systems and significantly induced the accumulation of polyubiquitinated proteins in PCa cells. The computational modeling analysis suggested that Mar non-covalently bound to active sites of proteasome β5 and β1 subunits, resulting in a non-competitive inhibition. Proteasome inhibition by Mar subsequently resulted in endoplasmic reticulum (ER) stress, as evidenced by elevated glucose-regulated protein 78 and CHOP, increased phospho-eukaryotic translation initiation factor 2α (eIF2α), splicing of X-box-binding protein-1 and dilation of the ER. However, Mar-mediated cell death was not completely impaired by a pan inhibitor of caspases. Further studies revealed that the Mar-induced cell death was greatly associated with the activation of autophagy, as indicated by the significant induction of microtubule-associated protein-1 light chain-3 beta (LC3B) expression and conversion. Electron microscopic and green fluorescent protein-tagged LC3B analyses further demonstrated the ability of autophagy induction by Mar. Time kinetic studies revealed that Mar induced a rapid and highly sustained processing of LC3B in treated cells and simultaneously decreased the expression of p62/SQSTM1. Pharmacological blockade or knockdown of LC3B and Atg5 attenuated Mar-mediated cell death. The autophagic response triggered by Mar required the activation of RNA-dependent protein kinase-like ER kinase/eIF2α and suppression of the phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin axis via preventing activation and expression of Akt. Our results identified a novel mechanism for the cytotoxic effect of Mar, which strengthens it as a potential agent in cancer chemotherapy.

Trends in incidence and prevalence of hypertension are grave in China and identifying high-risk, non-hypertension individuals for intervention may delay hypertension onset. We aimed to investigate the incidence of hypertension in northern urban Han Chinese population and construct multivariable hypertension prediction models through the prospective cohort, which included 7537 men and 4960 women free of hypertension at baseline between 2005 and 2010. During 38 958 person-years of follow-up, 2785 participants (men, 72.57%; women, 27.43%) developed hypertension. The incidence density of hypertension was 71.48 per 1000 person-year. In multivariable backward cox analyses, age, body mass index, systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting blood glucose and current drinking were retained for both men and women, while gamma-glutamyl transferase only for men, total cholesterol, neutrophil granulocyte and current smoking only for women. The area under receiver operating characteristic curve (AUC) was 0.761 (95% confidence interval (CI), 0.752-0.771) for men and 0.753 (95% CI, 0.741-0.765) for women, even after 10-fold cross-validation, the AUC was 0.760 (95% CI, 0.751-0.770) for men and 0.749 (95% CI, 0.737-0.761) for women. Through risk stratification, the absolute risk of incident hypertension in 5 years at moderate, high and very high risk level was 2.13, 3.84 and 6.14 times that of those who were at low risk in men, and 1.30, 2.56 and 6.01 times that of those who were at low risk in women. Our findings identified predictors of incident hypertension and indicated that the sex-specific multivariable prediction models would be simply used to estimate the risk of incident hypertension.

As one of the representative ABO 3 perovskite-structured oxides, lanthanum aluminate (LaAlO 3 ) crystal has emerged as one of the most valuable functional-materials, and has attracted plenty of fundamental research and promising applications in recent years. Electronic, magnetic, optical and other properties of LaAlO 3 strongly depend on its crystal structure, which could be strongly modified owing to the nuclear or electronic energy loss deposited in an ion irradiation environment and, therefore, significantly affecting the performance of LaAlO 3 -based devices. In this work, utilizing swift (tens of MeV) Si-ion irradiation, the damage behavior of LaAlO 3 crystal induced by nuclear or electronic energy loss has been studied in detail utilizing complementary characterization techniques. Differing from other perovskite-structured crystals in which the electronic energy loss could lead to the formation of an amorphous region based on the thermal spike mechanism, in this case, intense electronic energy loss in LaAlO 3 will not induce any obvious structural damage. The effects of ion irradiation on the mechanical properties, including hardness increase and elastic modulus decrease, have been confirmed. On the other hand, considering the potential applications of LaAlO 3 in the field of integrated optoelectronics, the optical-waveguide properties of the irradiation region have been studied. The significant correspondence (symmetrical inversion) between the iWKB-reconstructed refractive-index profile and SRIM-simulated dpa profile further proves the effects (irradiation-damage production and refractive-index decrease) of nuclear energy loss during the swift-ion penetration process in LaAlO 3 crystal. In the case of the rather-thick damage layer produced by swift-ion irradiation, obtaining a damage profile will be constrained owing to the analysis-depth limitation of the characterization techniques (RBS/channeling), and our analysis process (optical guided-mode measurement and subsequent refractive-index-profile reconstruction) also provides a new approach to study the damage behavior (damage profile) once the functional relationship between the refractive index and lattice disorder for the specific material could be determined.