No abstract

No abstract

Pancreatitis is an inflammatory disease that is responsible for substantial morbidity and mortality, and it can induce pancreatic necrosis that starts within pancreatic acinar cells in severe cases. Emodin, a pleiotropic natural product isolated from the Chinese herb Rheum palmatum L., has effective anti-inflammatory activities. In this paper, we investigated the protective effects and molecular mechanism of emodin against sodium taurocholate (STC)-induced pancreatic acinar cells injury in vitro and in vivo; and the results showed that emodin could significantly alleviate STC-induced pancreatic acinar cells injury through decreasing trypsin, amylase and the release of inflammatory factors (tumor necrosis factor alpha, interleukin-1β, and interleukin-6). Also, we found that emodin could significantly downregulate the HTRA1, interleukin-33, myeloid differentiation primary response gene 88, TNF receptor-associated factor-6, and nuclear factor kappa-B protein levels, but upregulate the transforming growth factor beta 1 (TGF-β1) protein level. These results indicated that emodin alleviated pancreatic acinar cells injury mainly through inhibiting HTRA1/TGF-β1 signaling pathway, and this finding was further proved by the HTRA1 overexpression experiments. In addition, the inflammatory regulator microRNA-30a-5p (miR-30a-5p) was confirmed to be a transcriptional brake that controls the HTRA1 gene through using a dual luciferase reporter assay, and it was upregulated by emodin in pancreatic acinar cells. Furthermore, the pancreatic protective effects and anti-inflammatory activities of emodin were all abrogated with both miR-30a-5p inhibitor in vitro and miR-30a-5p antagomir in vivo. Collectively, these results demonstrate that miR-30a-5p/HTRA1 are the target of emodin-mediated attenuation of pancreatic acinar cell injury in pancreatitis, thus providing the foundation for further development of this natural product for medical therapy.

No abstract

BackgroundThe development of multidrug resistance is a major problem in the treatment of pathogenic microorganisms by distinct antimicrobial agents. Characterizing the genetic variation among plasmids from different bacterial species or strains is a key step towards understanding the mechanism of virulence and their evolution.ResultsWe applied a deep sequencing approach to 206 clinical strains of Klebsiella pneumoniae collected from 2002 to 2008 to understand the genetic variation of multidrug resistance plasmids, and to reveal the dynamic change of drug resistance over time. First, we sequenced three plasmids (70 Kb, 94 Kb, and 147 Kb) from a clonal strain of K. pneumoniae using Sanger sequencing. Using the Illumina sequencing technology, we obtained more than 17 million of short reads from two pooled plasmid samples. We mapped these short reads to the three reference plasmid sequences, and identified a large number of single nucleotide polymorphisms (SNPs) in these pooled plasmids. Many of these SNPs are present in drug-resistance genes. We also found that a significant fraction of short reads could not be mapped to the reference sequences, indicating a high degree of genetic variation among the collection of K. pneumoniae isolates. Moreover, we identified that plasmid conjugative transfer genes and antibiotic resistance genes are more likely to suffer from positive selection, as indicated by the elevated rates of nonsynonymous substitution.ConclusionThese data represent the first large-scale study of genetic variation in multidrug resistance plasmids and provide insight into the mechanisms of plasmid diversification and the genetic basis of antibiotic resistance.