KLF4 down-regulation resulting from TLR4 promotion of ERK1/2 phosphorylation underpins inflammatory response in sepsis.

Sepsis is a systemic inflammatory response to invading pathogens, leading to high mortality rates in intensive care units worldwide. Krüppel-like factor 4 (KLF4) is an important anti-inflammatory transcription factor. In this study, we investigate the anti-inflammatory role of KLF4 in caecal ligation and puncture (CLP)-induced septic mice and lipopolysaccharide (LPS)-induced RAW264.7 cells and its potential mechanism. We found that KLF4 was down-regulated in CLP-induced septic mice and in LPS-induced RAW264.7 cells, and that its overexpression led to increased survival rates of septic mice along with inhibited inflammatory response in vivo and in vitro. ITGA2B was up-regulated in the setting of sepsis and was inhibited by KLF4 overexpression. ITGA2B knock-down mimicked the effects of KLF4 overexpression on septic mice and LPS-induced RAW264.7 cells. TLR4 promoted the phosphorylation of ERK1/2 and then up-regulated the ubiquitination and the degradation of KLF4, thereby elevating the expression of ITGA2B. Moreover, TLR4 knock-down or treatment with PD98059 (a MEK inhibitor) inhibited inflammatory response in the setting of sepsis in vivo and in vitro. Furthermore, this effect of PD98059 treatment was lost upon KLF4 knock-down. Collectively, these results explain the down-regulation of KLF4 in sepsis, namely via TLR4 promotion of ERK1/2 phosphorylation, and identify ITGA2B as the downstream gene of KLF4, thus highlighting the anti-inflammatory role of KLF4 in sepsis.

Genomic incompatibilities in the diploid and tetraploid offspring of the goldfish × common carp cross.

Polyploidy is much rarer in animals than in plants but it is not known why. The outcome of combining two genomes in vertebrates remains unpredictable, especially because polyploidization seldom shows positive effects and more often results in lethal consequences because viable gametes fail to form during meiosis. Fortunately, the goldfish (maternal) × common carp (paternal) hybrids have reproduced successfully up to generation 22, and this hybrid lineage permits an investigation into the genomics of hybridization and tetraploidization. The first two generations of these hybrids are diploids, and subsequent generations are tetraploids. Liver transcriptomes from four generations and their progenitors reveal chimeric genes (>9%) and mutations of orthologous genes. Characterizations of 18 randomly chosen genes from genomic DNA and cDNA confirm the chimera. Some of the chimeric and differentially expressed genes relate to mutagenesis, repair, and cancer-related pathways in 2nF1. Erroneous DNA excision between homologous parental genes may drive the high percentage of chimeric genes, or even more potential mechanisms may result in this phenomenon. Meanwhile, diploid offspring show paternal-biased expression, yet tetraploids show maternal-biased expression. These discoveries reveal that fast and unstable changes are mainly deleterious at the level of transcriptomes although some offspring still survive their genomic abnormalities. In addition, the synthetic effect of genome shock might have resulted in greatly reduced viability of 2nF2 hybrid offspring. The goldfish × common carp hybrids constitute an ideal system for unveiling the consequences of intergenomic interactions in hybrid vertebrate genomes and their fertility.

Yunnan Black Tea Flavonoids Can Improve Cognitive Dysfunction in Septic Mice by Activating SIRT1.

This study explored the effect and mechanism of Yunnan black tea flavonoids (YBTF) on cognitive dysfunction in septic mice. The mice were induced sepsis, the serum was determined using kits, and the tissue was determined by qPCR assay. The Yunnan black tea flavonoids were checked using HPLC. The test results showed that compared with the model group, YBTF could increase the survival rate of the mice; meanwhile, YBTF could also increase the total distance travelled, number of stands, and number of groomings, as well as the number of times crossing the area in the target quadrant. Detection of nerve cells showed that YBTF could reduce the rate of nerve cell apoptosis caused by sepsis. YBTF also reduced the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1ß), and malondialdehyde (MDA) in the hippocampus of septic mice and increased the activity of superoxide dismutase (SOD) and catalase (CAT) enzymes. YBTF could also upregulate the mRNA expression of SOD1, SOD2, CAT, and forkhead box O1 (FOXO1) and downregulate the mRNA expression of TNF-α, IL-1ß, nuclear factor kappa-B (NF-κB), p53, and SIRT1 in the hippocampus of septic mice. The animal experiment results showed that YBTF could improve the cognitive dysfunction of septic mice. The effect of YBTF was weaker than that of dexamethasone, but it could enhance the improvement effect when used in conjunction with dexamethasone. The component analysis results showed that YBTF contained 9 compounds, including catechin, gallocatechin gallate, rutin, hyperoside, epicatechin gallate, dihydroquercetin, quercetin, myricetin, and sulphuretin. From these results, YBTF could activate SIRT1 through its active compound components to improve the cognitive dysfunction of septic mice.

Lactobacillus casei Strain Shirota Enhances the Ability of Geniposide to Activate SIRT1 and Decrease Inflammation and Oxidative Stress in Septic Mice.

Gardenia jasminoides Ellis is rich in geniposide, which can be transformed into the anti-oxidant and anti-inflammatory agent genipin. Genipin exhibits greater efficacy than geniposide, but it is unstable and difficult to preserve. In this study, a mouse model for sepsis was established by cecal ligation and puncture, and then we explored the effects and mechanism of Lactobacillus casei strain Shirota (LcS) on the enhancement of the ability of geniposide to reduce sepsis and decrease inflammatory and oxidative levels in mice by the regulation of sirtuin type 1 (SIRT1). The mice were evaluated and analyzed by the open field test, Morris water maze test, flow cytometry, kit assay, qPCR, and western blot. The LcS + geniposide increased the survival rate in mice with sepsis, and increased the total travel distance, number of times the mice stood up, amount of time the mice spent grooming their fur, duration in the target quadrant, and crossing area number. The testing of mouse nerve cells showed that LcS + geniposide reduced the rate of nerve cell apoptosis caused by sepsis. LcS + geniposide also decreased the amount of inflammatory-related indicators of TNF-α, IL-6, and IL-1ß, and the oxidation-related levels of malondialdehyde (MDA) in the hippocampi of septic mice, and it increased the oxidase activities of superoxide dismutase (SOD) and catalase (CAT). Additionally, LcS + geniposide increased the SOD1, SOD2, and CAT mRNA expression in the hippocampi of mice with sepsis and decreased the expression of TNF-α, IL-1ß, NF-κB, and p53 mRNA. LcS+geniposide also increased the SIRT1 protein expression and decreased the Ac-FOXO1, Ac-NF-κB, and Ac-p53 protein expression in the hippocampi of mice with sepsis. We also observed that LcS + geniposide decreased the inflammatory and oxidative damage in the mice with sepsis. The effect of LcS + geniposide was similar to that of the drug dexamethasone and stronger than the effect of geniposide utilized alone. LcS also enhanced the ability of geniposide to activate SIRT1 and decrease the inflammation and oxidative stress in the septic mice, and it achieved an effect same with that obtained by the use of the drug dexamethasone.

VennPainter: A Tool for the Comparison and Identification of Candidate Genes Based on Venn Diagrams.

VennPainter is a program for depicting unique and shared sets of genes lists and generating Venn diagrams, by using the Qt C++ framework. The software produces Classic Venn, Edwards' Venn and Nested Venn diagrams and allows for eight sets in a graph mode and 31 sets in data processing mode only. In comparison, previous programs produce Classic Venn and Edwards' Venn diagrams and allow for a maximum of six sets. The software incorporates user-friendly features and works in Windows, Linux and Mac OS. Its graphical interface does not require a user to have programing skills. Users can modify diagram content for up to eight datasets because of the Scalable Vector Graphics output. VennPainter can provide output results in vertical, horizontal and matrix formats, which facilitates sharing datasets as required for further identification of candidate genes. Users can obtain gene lists from shared sets by clicking the numbers on the diagram. Thus, VennPainter is an easy-to-use, highly efficient, cross-platform and powerful program that provides a more comprehensive tool for identifying candidate genes and visualizing the relationships among genes or gene families in comparative analysis.