关键词： histone deacetylase 6 inhibitor   colitis   inflammatory bowel disease   anti-inflammatory activity  

摘要： Inflammatory bowel disease (IBD) is a refractory illness with remarkably increasing incidence rate all over the world. However, no desirable treatment scheme is available. Therefore, research and development of new drugs for treating IBD are urgently needed. Histone deacetylase 6 (HDAC6) is considered to be a pro inflammatory factor, thus the inhibitors specifically-targeting HDAC6 may find their way in IBD treatment. In this study, we evaluated the anti-inflammatory activity of a novel potent and selective HDAC6 inhibitor, LTB2, in dextran sulfate sodium (DSS)-induced colitis mouse model. It was found that LTB2 treatment significantly alleviated DSS-induced colitis in mice, as evidenced by body weight, colon length, histological examination, and the disease activity index (DAI) scores of rectal bleeding and diarrhea. More importantly, it showed a better protective effect on the DSS-induced colitis mice than the commonly used mesalazine in the clinic. Our results demonstrated that selective HDAC6 inhibitors may have a good prospect for IBD treatment.

关键词： Cell-free DNA   DSS-colitis   TLR9   Beclin1   ATG16L1   LC3B   Autophagy   Inflammation   Spleen index  

摘要： Background: The influence of cell-free DNA (fDNA) administration on the TLR9-autophagy regulatory crosstalk within inflammatory circumstances remains unclear. Aims: To examine the immunobiologic effects of iv. fDNA injection on the TLR9-mediated autophagy response in murine DSS-colitis. Methods: Different types of modified fDNAs were administered to DSS-colitic mice. Disease and histological activities, spleen index were measured. Changes of the TLR9-associated and autophagy-related gene expression profiles of lamina proprial cells and splenocytes were assayed by quantitative real-time PCR, and validated by immunohistochemistries. Ultrastructural changes of the colon were examined by transmission electron microscopy (TEM). Results: A single intravenous injection of colitic fDNA (C-DNA) exhibited beneficial clinical and histological effects on DSS-colitis, compared to normal (N-DNA). C-DNA administration displayed a more prominent impact on the outcome of the TLR9-autophagy response than N-DNA. C-DNA resulted in a decreased spleen index in DSS-colitic mice. C-DNA treatment of normal mice resulted in a downregulation of Beclin1 and ATG16L1 mRNA and protein expression in the colon. These as well as LC3B were downregulated in the spleen. In contrast, the Beclin1, ATG16L1 and LC3B gene and protein expressions were upregulated in both the colon and the spleen by C-DNA injection. Moreover, C-DNA administration to DSS-colitic mice resulted in a remarkable increase of epithelial autophagic vacuoles representing an intensified macroautophagy. Conclusions: The effect of intravenously administered fDNA on the TLR9-mediated autophagy response is expressly dependent on the origin of fDNA (i.e. inflammatory or not) and on the characteristics of the local immunobiologic milieu (i.e. inflammatory or not, as well).

关键词： adrenomedullin   PEGylation   inflammatory bowel disease   colitis  

摘要： Human adrenomedullin (hAM), a hypotensive peptide, also has anti-inflammatory effects. hAM can reduce the severity of the dextran sulphate sodium (DSS)- and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in animal models. Furthermore, in a clinical study, hAM treatment reduced the Disease Activity Index in ulcerative colitis. However, these therapeutic effects required continuous administration of hAM as the half-life of native hAM is quite short in blood. To resolve this problem, hAM N-terminal was conjugated with two kinds of polyethylene glycol (PEG);5 kDa PEG or 60 kDa PEG (5 kDa PEG-hAM and 60 kDa PEG-hAM respectively). In a previous study, 5 kDa PEG-hAM stimulated cAMP production and prolonged the plasma half-life compared with native hAM. Herein we examine the effect of PEG-hAM in the DSS colitis model. Treatment with both PEG-hAM preparations reduced the total inflammation score. In addition, the plasma half-life of 60 kDa PEG-hAM was much longer than 5 kDa PEG-hAM. In summary, a single subcutaneous administration of 60 kDa PEG-hAM reduced the total inflammation score in mice with DSS-induced colitis. Therefore, these results suggest that 60 kDa PEG-hAM is a possible therapeutic agent for the treatment of inflammatory bowel disease. Drug Dev Res 78 : 129-134, 2017. (c) 2017 Wiley Periodicals, Inc.

摘要： Ulcerative colitis is a multi-factorial disease involving a dysregulated immune response. Disruptions to the intestinal epithelial barrier and translocation of bacteria, resulting in inflammation, are common in colitis. The mechanisms underlying epithelial barrier dysfunction or regulation of tight junction proteins during disease progression of colitis have not been clearly elucidated. Increase in phospholipase D (PLD) activity is associated with disease severity in colitis animal models. However, the role of PLD2 in the maintenance of intestinal barrier integrity remains elusive. We have generated intestinal specific Pld2 knockout mice (Pld2 IEC-KO) to investigate the mechanism of intestinal epithelial PLD2 in colitis. We show that the knockout of Pld2 confers protection against dextran sodium sulphate (DSS)-induced colitis in mice. Treatment with DSS induced the expression of PLD2 and downregulated occludin in colon epithelial cells. PLD2 was shown to mediate phosphorylation of occludin and induce its proteasomal degradation in a c-Src kinase-dependent pathway. Additionally, we have shown that treatment with an inhibitor of PLD2 can rescue mice from DSS-induced colitis. To our knowledge, this is the first report showing that PLD2 is pivotal in the regulation of the integrity of epithelial tight junctions and occludin turn over, thereby implicating it in the pathogenesis of colitis.

关键词： 港口   生产调度   大数据分析   智能分析   决策支持  

摘要： 为优化港口调度模式、提升港口调度效率,在全面整合港口调度信息资源的基础上,建立调度数据分析模型,并运用Tableau BI软件和大数据分析技术建立港口生产调度大数据分析平台,从多个维度智能分析调度过程,评价调度方案,加速调度信息反馈。该平台为港口管理人员提供在线决策支持,有效提升港口调度方案的实效性和科学性。

关键词： 综合集成研讨厅   初始水权分配   综合集成型决策支持系统  

摘要： 为了更好解决由于传统初始水权分配中现存的效率不足、无法兼顾各利益主体间的公平、配置方法存在局限性以及配套法律不完善等问题,引申出的一系列复杂决策问题,根据其求解的综合集成过程关注到对系统的需求,并制定出一种综合集成型决策支持系统,借鉴钱学森提出的解决复杂性巨系统问题的综合集成理论,构建初始水权分配综合集成研讨厅作为决策平台。