RIP3 blockade prevents immune-mediated hepatitis through a myeloid-derived suppressor cell dependent mechanism

Autoimmune hepatitis (AIH) is an immune-mediated chronic inflammatory liver disease, and its pathogenesis is not fully understood. Our previous study discovered that receptor interacting protein kinase 3 (RIP3) is correlated with serum transaminase levels in AIH patients. However, its role and underlying mechanism in AIH are poorly understood. Here, we detected the increased expression and activation of RIP3 in livers of patients and animal models with AIH. The inhibition of RIP3 kinase by GSK872 prevented concanavalin A (ConA)-induced immune-mediated hepatitis (IMH) by reduced hepatic proinflammatory cytokines and immune cells including Th17 cells and macrophages. Further experiments revealed that RIP3 inhibition resulted in an increase in CD11b⁺Gr1⁺ myeloid-derived suppressor cells (MDSCs) with immunoregulatory properties in the liver, spleen, and peripheral blood. Moreover, the depletion of Gr-1⁺ MDSCs abrogated the protective effect and immune suppression function of GSK872 in ConA-induced IMH. Altogether, our data demonstrate that RIP3 blockade prevents ConA-induced IMH through promoting MDSCs infiltration. Inhibition of RIP3 kinase may be a novel therapeutic avenue for AIH treatment.     

CD137-mediated pathogenesis from chronic hepatitis to hepatocellular carcinoma in hepatitis B virus-transgenic mice

Chronic hepatitis B virus (HBV) infection is characterized by sustained liver inflammation with an influx of lymphocytes, which contributes to the development of cirrhosis and hepatocellular carcinoma. The mechanisms underlying this immune-mediated hepatic pathogenesis remain ill defined. We report in this article that repetitive infusion of anti-CD137 agonist mAb in HBV-transgenic mice closely mimics this process by sequentially inducing hepatitis, fibrosis, cirrhosis, and, ultimately, liver cancer. CD137 mAb initially triggers hepatic inflammatory infiltration due to activation of nonspecific CD8(+) T cells with memory phenotype. CD8(+) T cell-derived IFN-γ plays a central role in the progression of chronic liver diseases by actively recruiting hepatic macrophages to produce fibrosis-promoting cytokines and chemokines, including TNF-α, IL-6, and MCP-1. Importantly, the natural ligand of CD137 was upregulated significantly in circulating CD14(+) monocytes in patients with chronic hepatitis B infection and closely correlated with development of liver cirrhosis. Thus, sustained CD137 stimulation may be a contributing factor for liver immunopathology in chronic HBV infection. Our studies reveal a common molecular pathway that is used to defend against viral infection but also causes chronic hepatic diseases.     

Genome-wide analysis of mammalian DNA segment fusion/fission

As a powerful tool for gene function prediction, gene fusion has been widely studied in prokaryotes and certain groups of eukaryotes, but it has been little applied in studies of mammalian genomes. With the first fully sequenced mammalian genomes (human, mouse, rat) now available, we defined and collected a set of fusion/fission event-linked segments (FFLS) based on structured organized genomic alignment. The statistics of the sequence features highlighted the FFLSs against their random context. We found that there are three groups of FFLSs with different component pairs (i.e. gene-gene, gene-noncoding and noncoding-noncoding) in all three mammalian genomes. The proteins encoded by the components of FFLSs in the first group shown a strong tendency to interact with each other. The segmental components in the last two groups which did not contain any protein-coding genes, were found not only to be transcribed to some level, but also more conserved than the random background. Thus, these segments are possibly carrying certain biologically functional elements. We propose that FFLS may be a potential tool for prediction and analysis of function and functional interaction of genetic elements, including both genes and noncoding elements, in mammalian genomes. The full list of the FFLSs in the genomes of the three mammals is available as supporting information at doi:10.1016/j.jtbi.2005.09.016.     

VO(2) kinetics reveal a central limitation at the onset of subthreshold exercise in heart transplant recipients.

Because the cardiocirculatory response of heart transplant recipients (HTR) to exercise is delayed, we hypothesized that their O(2) uptake (VO(2)) kinetics at the onset of subthreshold exercise are slowed because of an impaired early "cardiodynamic" phase 1, rather than an abnormal subsequent "metabolic" phase 2. Thus we compared the VO(2) kinetics in 10 HTR submitted to six identical 10-min square-wave exercises set at 75% (36 +/- 5 W) of the load at their ventilatory threshold (VT) to those of 10 controls (C) similarly exercising at the same absolute (40 W; C40W group) and relative load (67 +/- 14 W; C67W group). Time-averaged heart rate, breath-by-breath VO(2), and O(2) pulse (O(2)p) data yielded monoexponential time constants of the VO(2) (s) and O(2)p increase. Separating phase 1 and 2 data permitted assessment of the phase 1 duration and phase 2 VO(2) time constant (). The VO(2) time constant was higher in HTR (38.4 +/- 7.5) than in C40W (22.9 +/- 9.6; P < or = 0. 002) or C67W (30.8 +/- 8.2; P < or = 0.05), as was the O(2)p time constant, resulting from a lower phase 1 VO(2) increase (287 +/- 59 vs. 349 +/- 66 ml/min; P < or = 0.05), O(2)p increase (2.8 +/- 0.6 vs. 3.6 +/- 1.0 ml/beat; P < or = 0.0001), and a longer phase 1 duration (36.7 +/- 12.3 vs. 26.8 +/- 6.0 s; P < or = 0.05), whereas the was similar in HTR and C (31.4 +/- 9.6 vs. 29.9 +/- 5.6 s; P = 0.85). Thus the HTR have slower subthreshold VO(2) kinetics due to an abnormal phase 1, suggesting that the heart is unable to increase its output abruptly when exercise begins. We expected a faster in HTR because of their prolonged phase 1 duration. Because this was not the case, their muscular metabolism may also be impaired at the onset of subthreshold exercise.     

DNA疫苗的分子佐剂应用研究进展

DNA疫苗因在动物尤其是大型动物与人类中诱发较低的免疫反应而严重影响其推广应用。介绍提高与调节DNA疫苗诱导反应的策略：（1）以细胞因子表达质控为佐剂;（2）以质粒编码的趋化因子与共刺激分子为佐剂;（3）以CPG ODN为佐剂。     

Expression of apoptosis-related genes in the endometrium of polycystic ovary syndrome patients during the window of implantation

The present study investigated the expression of the apoptosis-related genes fas-associated via death domain (FADD) and Bcl-2 in the endometrium during the window of implantation in polycystic ovary syndrome (PCOS) patients. The aim was to explore the role of cell apoptosis in endometrial receptivity during this period. The subjects were divided into experimental and control group. The experimental group comprised 12 infertile women with PCOS, and the control group comprised 12 women who were infertile because of tubal pathological factors but had normal menstrual cycles. Endometria were collected by biopsy 7d after ovulation. Six samples from each group were randomly selected and subjected to gene chip analyses. The expression of endometrial FADD and Bcl-2 was determined by immunohistochemistry, and cell apoptosis was detected by the TUNEL method. Compared with the control group, 194 differentially expressed genes were found in the PCOS group, 102 of which were upregulated and 92 were downregulated. The differentially expressed genes were divided into 15 types according to function. Among the nine genes related to cell apoptosis, five (including Bcl-2) were upregulated and four were downregulated (including FADD). Bcl-2 expression during the window of implantation in the PCOS group increased compared with the control group, showing a significant difference (P<0.05). FADD expression in the PCOS group notably decreased compared with that in the control group, which also showed a significant difference (P<0.05). Cell apoptosis analysis showed a significant difference between the average apoptotic indices in the PCOS and control groups (P<0.05). Significant differences were observed between the endometrial gene expression in the PCOS and control groups. The decrease in cell apoptosis during the window of implantation in PCOS patients may be one of the causes of the reduced endometrial receptivity.     

Effects of copper enrichment on survival,growth and photosynthetic pigment of seedlings and young plants of the eelgrass Zostera marina

Copper (Cu²⁺) is an essential nutrient for plants but toxic at high concentrations. We subjected seedlings and young plants of eelgrass Zostera marina to different seawater Cu concentrations (3, 4, 5, 10, 30 and 50?µg?l^?1) for over 30 days under controlled laboratory conditions. Natural seawater without added Cu (3?µg?l^?1) was used as reference seawater. We measured plant response in terms of survivorship, morphology, growth, productivity and leaf pigment concentration. Survival analysis combined with morphological, dynamic and productive assessment suggested that the optimum seawater Cu concentration for the establishment of Z. marina seedlings and young plants is 4?μg?l^?1. The photosynthetic response of young plants to copper enrichment, including an increase in chlorophyll content under low Cu concentration treatment but significant decrease when treated with high concentrations of Cu, is similar to those reported for other seagrass species. NOEC (no observed effect concentration), LOEC (lowest observed effect concentration) and LC₅₀ (lethal concentration that caused an increase in mortality to 50% of that of the control) values of seedlings were significantly lower than those of young plants, implying a reduced Cu tolerance to high concentrations (>10?μg?l^?1). This study provides data that could prove helpful in the development of successful eelgrass restoration and conservation.