Xinshubao tablet ameliorates myocardial injury against heart failure via the DCN/PPARα/PGC-1α/P300 pathway

Heart failure (HF) is a complex clinical syndrome with impaired ventricular ability due to structural or functional cardiac disorders. A traditional Chinese formula named Xinshubao tablet (XSB) is reported to protect cardiomyocytes and decrease the risk of HF clinically; however, the underlying mechanism of XSB on decreasing HF risk is not elucidated yet. Therefore, our study aimed to investigate the therapeutic efficacy and underlying mechanism of XSB by using HF model rats and H9c2 cells with oxygen glucose deprivation. Echocardiographic and pathological features of animal experiment showed that XSB treatment effectively improved cardiac function and ameliorated myocardial injury after 4 weeks of treatment. Cellular experiments indicated that XSB pretreatment significantly inhibited apoptosis and increased mitochondrial energy metabolism. Furthermore, in vivo and in vitro experiments both demonstrated that XSB suppressed oxidative stress and inflammatory response. Our results further revealed that the potential protective mechanism of XSB was closely associated with the DCN/PPARα/PGC-1α/P300 signaling pathway. Our findings provide novel mechanistic insights for HF treatment and a pharmacological basis for the therapeutic application of XSB against cardiovascular disorders

Selumetinib, an Oral Anti-Neoplastic Drug, May Attenuate Cardiac Hypertrophy via Targeting the ERK Pathway.

Although extracellular-regulated kinases (ERK) are a well-known central mediator in cardiac hypertrophy, no clinically available ERK antagonist has been tested for preventing cardiac hypertrophy. Selumetinib is a novel oral MEK inhibitor that is currently under Phase II and Phase III clinical investigation for advanced solid tumors. In this study, we investigated whether Selumetinib could inhibit the aberrant ERK activation of the heart in response to stress as well as prevent cardiac hypertrophy.In an in vitro model of PE-induced cardiac hypertrophy, Selumetinib significantly inhibited the ERK activation and prevented enlargement of cardiomyocytes or reactivation of certain fetal genes. In the pathologic cardiac hypertrophy model of ascending aortic constriction, Selumetinib provided significant ERK inhibition in the stressed heart but not in the other organs. This selective ERK inhibition prevented left ventricular (LV) wall thickening, LV mass increase, fetal gene reactivation and cardiac fibrosis. In another distinct physiologic cardiac hypertrophy model of a swimming rat, Selumetinib provided a similar anti-hypertrophy effect, except that no significant fetal gene reactivation or cardiac fibrosis was observed.Selumetinib, a novel oral anti-cancer drug with good safety records in a number of Phase II clinical trials, can inhibit ERK activity in the heart and prevent cardiac hypertrophy. These promising results indicate that Selumetinib could potentially be used to treat cardiac hypertrophy. However, this hypothesis needs to be validated in human clinical trials

Transcriptome Profiling of the Cancer, Adjacent Non-Tumor and Distant Normal Tissues from a Colorectal Cancer Patient by Deep Sequencing

<div><p>Colorectal cancer (CRC) is one of the most commonly diagnosed cancers in the world. A genome-wide screening of transcriptome dysregulation between cancer and normal tissue would provide insight into the molecular basis of CRC initiation and progression. Compared with microarray technology, which is commonly used to identify transcriptional changes, the recently developed RNA-seq technique has the ability to detect other abnormal regulations in the cancer transcriptome, such as alternative splicing, novel transcripts or gene fusion. In this study, we performed high-throughput transcriptome sequencing at ∼50× coverage on CRC, adjacent non-tumor and distant normal tissue. The results revealed cancer-specific, differentially expressed genes and differential alternative splicing, suggesting that the extracellular matrix and metabolic pathways are activated and the genes related to cell homeostasis are suppressed in CRC. In addition, one tumor-restricted gene fusion, PRTEN-NOTCH2, was also detected and experimentally confirmed. This study reveals some common features in tumor invasion and provides a comprehensive survey of the CRC transcriptome, which provides better insight into the complexity of regulatory changes during tumorigenesis.</p> </div

KEGG pathway of enriched differentially expressed genes.

<p>KEGG pathway of enriched differentially expressed genes.</p

Statistics of colorectal cancer transcriptome mapping to human genome Hg19.

<p>Statistics of colorectal cancer transcriptome mapping to human genome Hg19.</p

Analysis of differential exon skipping

<p>(<b>DES</b>) <b>events among samples.</b> A: Venn diagram of the number of DES events; B: The overlap between differentially expressed genes and genes with DES events.</p

Differential expression analysis of cancer, adjacent non-tumor and distant normal tissue.

<p>A: The scatter plot for global expression between samples; the Pearson correlation coefficient is shown; B: Hierarchical clustering of differentially expressed genes (DEGs) among samples; C: Venn diagram to illustrate the overlapped DEGs between samples; D: Volcano plots for all the genes in each comparison. The red and blue dots indicate that up- and down-regulated DEGs were significant at q values less than 0.01.</p

Cancer-associated differential splicing events in colorectal cancer.

&<p>: s1, s2 and s3 represented the normal, adjacent non-tumor and cancer tissues, respectively;</p>#<p>: Ψ, percentage spliced in, denotes the fraction of mRNAs that represent the inclusion isoform <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0041001#pone.0041001-Jiang1" target="_blank">[67]</a>;</p>*<p>: The “diff” is provided by the MISO, and indicated the degree of splicing difference between samples. It was in [−1, 1]. The positive “diff” value means that the exon was skipped less in the sample1 than that in the sample2, and the negative values means the exon skipped less in the sample2;</p>$<p>: The “bayes factor” is provided by MISO, indicating the significance of the splicing difference. It was in [0, +∞), and it was greater, then the difference was more significant.</p

Illustration of the PTGFRN-NOTCH2 gene fusion in cancer tissue.

<p>A: The inter-chromosomal gene fusion involves the PTGFRN (shown in yellow) and NOTCH2 (shown in green) loci; the distance between these two loci is about three Mbp. The fusion events were detected by pair-end reads that spanned the fusion region and reads that crossed the fusion region; B: The comparison of the reads mapping results for the fusion transcripts among the three samples. The structure of the fusion gene is at the bottom. The reads counts for “normal”, “adjacent non-tumor” and “cancer” tissue are denoted as “green”, “blue” and “red” bars, respectively. C: The RT-PCR with the sequencing results of the fusion transcript in the three samples. The PCR primer is marked in panel A. D: The prediction of ORF of and its function for PTGFRN-NOTCH2 by bioinformatics, The start codon was using the start codon of NOTCH2 and the stop codon (red “*”) located in the fusion sequence from PTGFRN. The fusion peptide contained the domains (predicted by CD-Search in NCBI) in its region from NOTCH2, like EGF domains, but some key domains in the protein NOTCH2, such as NOTCH domain and Ankyrin repeats, were missing.</p