It is well known that hepatitis B virus infections can be transient or chronic, but the basis for this dichotomy is not known. To gain insight into the mechanism responsible for the clearance of hepadnavirus infections, we have performed a molecular and histologic analysis of liver tissues obtained from transiently infected woodchucks during the critical phase of the recovery period. We found as expected that clearance from transient infections occurred subsequent to the appearance of CD4 ؉ and CD8 ؉ T cells and the production of interferon gamma and tumor necrosis factor alpha in the infected liver. These events were accompanied by a significant increase in apoptosis and regeneration of hepatocytes. Surprisingly, however, accumulation of virus-free hepatocytes was delayed for several weeks following this initial influx of lymphocytes. In addition, we observed that chronically infected animals can exhibit levels of T-cell accumulation, cytokine expression, and apoptosis that are comparable with those observed during the initial phase of transient infections. Our results are most consistent with a model for recovery predicting replacement of infected hepatocytes with regenerated cells, which by unknown mechanisms remain protected from reinfection in animals that can be cured.Human hepatitis B virus (HBV), as well as the related woodchuck hepatitis virus (WHV), can cause transient or chronic infections in its native host (11,24,27). The molecular basis for the dichotomy of disease outcomes is not known. As in humans, in woodchucks chronic, lifelong WHV infections generally occur when virus is transmitted during or soon after birth. Infection of adults leads to transient infections in over 90% of cases. Experiments with woodchucks have shown that clearance of infections can occur within a few weeks even when nearly all hepatocytes in the liver have been infected (14, 20). Thus, a major question concerns the molecular mechanism responsible for the regulation of clearance of virus from infected hepatocytes.Clearance from infections with noncytopathic viruses, such as hepadnaviruses, requires the elimination of infected cells by cytotoxic T lymphocytes (CTLs) and the production of neutralizing antibodies directed against one or several viral proteins (13). A role for T cells in the recovery from natural hepadnavirus infections has been demonstrated through treatment with cyclosporin A, a known suppressor of T-cell function, which prevents recovery from otherwise transient WHV infections in adult woodchucks (4). It also appears that the number of CTLs present in the peripheral blood of chronically infected patients is approximately 10 to 100 times lower than that in the blood of patients with transient infections (23), suggesting that a critical number of reactive CTLs are required for recovery. In this scenario all infected hepatocytes would have to be killed by CTLs and replaced by uninfected cells. In order to sustain sufficient liver function, the rate of cell death should not exceed the rate of cell replacement ov...

1Broncho-Vaxom (OM85-BV) is an extract mixture from 8 strains of Gram + and Gram -bacteria and plays an important role in anti-infection immune response by regulating macrophage activity and cytokine productions. However, the mechanism by which OM85-BV enhances the cytokine expression is still obscure. In this study, we evaluated the effects of OM85-BV on the productions of interleukin (IL)-1b, IL-6, and tumor necrosis factor-a (TNF-a) in RAW264.7 murine macrophages. Exposure of RAW264.7 cells to 100 mg/mL OM85-BV upregulated the expression of IL-1b, IL-6, and TNF-a at the mRNA and protein levels in a time-and dosedependent manner. In addition, OM85-BV induced extracellular signal-regulated kinase (ERK) 1/2 and nuclear factor-kappa B (NF-kB) phosphorylation. Pretreatment with U0126 or Bay11-7082, respectively, could decrease IL-1b, IL-6, and TNF-a productions induced by OM85-BV. Application of Toll-like receptor (TLR) 4 or TLR2 small-interfering RNA (siRNA) into RAW264.7 cells could inhibit the productions of cytokines and ERK1/2 and NF-kB phosphorylation induced by OM85-BV. Consistent with this, downregulating either myeloid differentiation factor 88 (MyD88) or TRIF-related adaptor molecule (TRAM) gene with MyD88-siRNA or TRAM-siRNA separately could reduce the productions of cytokines and ERK1/2 and NF-kB phosphorylation induced by OM85-BV. Our study demonstrated that the productions of IL-1b, IL-6, and TNF-a induced by OM85-BV in RAW264.7 cells were through TLR4 and TLR2 signaling pathway-mediated activation of ERK1/2 and NF-kB.

Cardiac remodeling is a self-regulatory response of the myocardium and vasculature under the stressful condition. Cardiomyocytes (CMs), vascular smooth muscle cells (VSMCs), endothelial cells (ECs), and cardiac fibroblasts (CFs) are all involved in this process, characterized by change of morphological structures and mechanical/chemical activities as well as metabolic patterns. Despite current development of consciousness, the control of cardiac remodeling remains unsatisfactory, and to further explore the underlying mechanism and seek the optimal therapeutic targets is still the urgent need in clinical practice. It is now emerging that long noncoding RNAs (lncRNAs) play key regulatory roles in these adverse responses: lncRNA TUG1, AK098656, TRPV1, GAS5, Giver, and Lnc-Ang362 have been indicated in hypertension-related vascular remodeling, H19, TUG1, UCA1, MEG3, APPAT, and lincRNA-p21 in atherosclerosis (AS), and HIF1A-AS1 and Lnc-HLTF-5 in aortic aneurysm (AA). In addition, Neat1, AK139328, APF, CAIF, AK088388, CARL, MALAT1, HOTAIR, XIST, and NRF are involved in postischemia myocardial remodeling, while Mhrt, Chast, CHRF, ROR, H19, Plscr4, and MIAT are involved in myocardial hypertrophy, and MALAT1, wisper, MEG3, and H19 are involved in extracellular matrix (ECM) reconstitution. Signaling to specific miRNAs by acting as endogenous sponge (ceRNA) was the main form that regulates the target gene expression during cardiac remodeling. This review will underline the updates of lncRNAs and lncRNA-miRNA interactions in maladaptive remodeling and also cast light on their potential roles as therapeutic targets, hoping to provide supportive background for following research.

Matrine, a clinical drug in China, has been used to treat viral hepatitis, cardiac arrhythmia and skin inflammations. Matrine also exhibits chemotherapeutic potential through its ability to trigger cancer cell death. However, the mechanisms involved are still largely unknown. The objective of this study was to investigate the major determinant for the cell death induced by matrine in human hepatocellular carcinoma. We use human hepatocellular carcinoma cell line HepG2 and human hepatocellular carcinoma xenograft in nude mice as models to study the action of matrine in hepatocellular cancers. We found that caspase-dependent and -independent Program Cell Death (PCD) occurred in matrine-treated HepG2 cells, accompanied by the decreasing of mitochondrial transmembrane potential and the increasing ROS production. Further studies showed that AIF released from the mitochondria to the nucleus, and silencing of AIF reduced the caspase-independent PCD induced by matrine. What’s more, AIF nuclear translocation, and the subsequent cell death as well, was prevented by Bid inhibitor BI-6C9, Bid-targeted siRNA and ROS scavenger Tiron. In the in vivo study, matrine significantly attenuated tumor growth with AIF release from mitochondria into nucleus in nude mice. These data imply that matrine potently induce caspase-independent PCD in HepG2 cells through Bid-mediated AIF translocation.

Our study confirmed the involvement of IL-17A in the development of intestinal fibrosis through inducing EMT.

Background/Aims: A disintegrin and metalloprotease (ADAM) 17 has been reported to be implicated in cancer cells invasion. Nevertheless, its potential role in lung adenocarcinoma has not been addressed clearly. Methods: RT-PCR and Western blot were used to detect the expression of miR-326 and ADAM17 in lung adenocarcinoma samples (n=73). miR-326 mimics and inhibitor were tansfected in human A549 and SPCA1 cell lines. The transwell assay was used to detect the cell invasive ability. The regulation mechanism was evaluated by luciferase reporter assay. The markers of (epithelial-to-mesenchymal transition) EMT were detected by using Western blot assay. Results: We found increased expression of ADAM17 in lung adenocarcinoma and cell lines. In vitro, up-regulation of ADAM17 promoted cells invasion, while silencing of ADAM17 inhibited cells invasion. Meanwhile, ADAM17 could affect the markers of EMT. Furthermore, we confirmed that ADAM17 is a target of miR-326, which is involved in EMT and cells invasion. Conclusions: These findings revealed that ADAM17, a target of miR-326, promoted EMT-induced cells invasion in lung adenocarcinoma.

Transforming growth factor-β1 (TGF-β1)-induced epithelial-mesenchymal transition (EMT) of non-small-cell carcinoma (NSCLC) may contribute to tumor metastasis. TGF-β1-induced EMT in H1975 cells (a human NSCLC cell line) resulted in the adoption of mesenchymal responses that were predominantly mediated via the TGF-β1-integrin signaling pathway. Ursolic acid has been previously reported to inhibit tumor growth and metastasis in several cancers. However, whether ursolic acid can attenuate TGF-β1-induced EMT in H1975 cells and its underlying mechanisms remains unknown. In this study, ursolic acid significantly attenuated the TGF-β1-induced decrease in E-cadherin level and elevated the level of N-cadherin. Furthermore, ursolic acid inhibited the mesenchymal-like responses in H1975 cells, including cell migration, invasion and activity of matrix metallopeptidase (MMP)-2 and -9. Finally, our new findings provided evidence that, ursolic acid could inhibit EMT in NSCLC through TGF-β1 signaling pathway mediated integrinαVβ5 expression, and this might the potential mechanism of resveratrol on the inhibition of invasion and metastases in NSCLC. We conclude that ursolic acid attenuated TGF-β1-induced EMT in H1975 cells and might be a promising therapeutic agent for treating NSCLC.

Summary In the traditional extended Kalman filter approach, unknown structural parameters are included in the extended state vector. Then, the sizes of the extended state vector and the corresponding state equation are quite large, and the state equation is highly nonlinear with respect to the extended state vector. This may cause identification divergent for a large number of unknown parameters. Also, such strategy requires large computational effort and storage capacities, which is not appropriate for intelligent structural damage detection implemented by smart sensors with microprocessors. In this paper, an algorithm based on a two‐step Kalman filter approach is proposed to remove the aforementioned drawbacks of the traditional extended Kalman filter. In the first step, recursive estimation of structural state vector is derived by Kalman filter with assumed structural parameters. In the second step, structural parameters and the updated structural state vector are estimated by the Kalman filter and the recursive estimation in the first step. Thus, the number of estimated variables in each step is reduced, which reduces the computational effort and storage requirements. This superiority is important for intelligent structural damage detection implemented by smart sensor in wireless sensor network. The proposed algorithm is first validated by numerical simulations results of structural damage detection of the phase‐I 3‐D ASCE benchmark building for structural health monitoring, a 30‐story shear building with minor damage, and an experimental test of damage detection of a lab multistory frame model. Then, it is applied to structural damage detection of a lab multistory model‐employed smart sensors embedded with the proposed algorithm. Copyright © 2014 John Wiley & Sons, Ltd.