Postinfarction exercise training alleviates cardiac dysfunction and adverse remodeling via mitochondrial biogenesis and SIRT1/PGC-1α/PI3K/Akt signaling.

Exercise training mitigates cardiac pathological remodeling and dysfunction caused by myocardial infarction (MI), but its underlying cellular and molecular mechanisms remain elusive. Our present study in an in vivo rat model of MI determined the impact of post-MI exercise training on myocardial fibrosis, mitochondrial biogenesis, antioxidant capacity, and ventricular function. Adult male rats were randomized into: (a) Sedentary control group; (b) 4-week treadmill exercise training group; (c) Sham surgery group; (d) MI group with permanent ligation of left anterior descending coronary artery and kept sedentary during post-MI period; and (e) post-MI 4-week exercise training group. Results indicated that exercise training significantly improved post-MI left ventricular function and reduced markers of cardiac fibrosis. Exercise training also significantly attenuated MI-induced mitochondrial damage and oxidative stress, which were associated with enhanced antioxidant enzyme expression and/or activity and total antioxidant capacity in the heart. Interestingly, the adaptive activation of the SIRT1/PGC-1α/PI3K/Akt signaling following MI was further enhanced by post-MI exercise training, which is likely responsible for exercise-induced cardioprotection and mitochondrial biogenesis. In conclusion, this study has provided novel evidence on the activation of SIRT1/PGC-1α/PI3K/Akt pathway, which may mediate exercise-induced cardioprotection through reduction of cardiac fibrosis and oxidative stress, as well as improvement of mitochondrial integrity and biogenesis in post-MI myocardium.

N-myc downstream-regulated gene 2 promotes the protein stability of estrogen receptor beta via inhibition of ubiquitin-protein ligase E3A to suppress colorectal cancer.

BACKGROUND: N-myc downstream-regulated gene 2 (NDRG2) and estrogen receptor beta (ERß) both play key roles in cellular differentiation in colorectal cancer (CRC). Previous studies have demonstrated that ERß co-locates with and directly transactivates NDRG2. However, the effect of NDRG2 on ERß and its underlying mechanism remain largely unknown. Our aim of the study is to explore the effect of NDRG2 on ERß and their contributions to progression of CRC. METHODS: The Cancer Genome Atlas (TCGA) database was first utilized to validate the clinical significance of ERß and NDRG2 in CRC. MTT and scratch migration assays were carried out to verify the role of ERß and NDRG2 in CRC cells. Western blotting and polymerase chain reaction were performed to analyze the effect of NDRG2 on ERß, and an immunoprecipitation assay was conducted to explore the protein-protein interaction. RESULTS: ERß and NDRG2 were both found to be significantly down-regulated in tumor tissues from the TCGA-CRC database. NDRG2 was also observed to enhance the protein stability of ERß while could not change messenger RNA (mRNA) level of ESR2 (encoding ERß). A positive relationship was found to exist between the two proteins in CRC cells, with NDRG2 prolonging the half-life of ERß and improving its nuclear translocation. Through detecting expression of ERß downstream genes (such as TP53 and JNK) and performing related function experiment, we demonstrated that NDRG2 could promote transcriptional activation of ERß target genes and enhance the function of tumor suppressors when the ERß agonist diarylpropionitrile (DPN). The immunoprecipitation assay showed that NDRG2 could affect the complex components of ubiquitin-protein ligase E3A (UBE3A, known as E6AP) and ERß, reducing the ubiquitin-mediated proteasome degradation of ERß. CONCLUSIONS: In the current study, we found that NDRG2 could bind with UBE3A to hinder the binding of UBE3A with ERß. Moreover, a positive feedback loop was discovered between NDRG2 and ERß, which provides a novel insight and therapeutic target for CRC.

A novel YAP1/SLC35B4 regulatory axis contributes to proliferation and progression of gastric carcinoma.

Solute carrier family 35 member B4 (SLC35B4), a nucleotide sugar transporter, is capable of transporting UDP-xylose and UDP-GlcNAc from the cytoplasm to the lumen of the endoplasmic reticulum and Golgi. SLC35B4 has a pivotal role in glycosylation of biological macromolecules. However, its functional roles and regulatory mechanisms in malignant diseases remain unknown. Here, using the cDNA arrays, promoter reporter assays, and chromatin immunoprecipitation assays, we demonstrated that SLC35B4 is directly transactivated by YAP1-TEADs complex in gastric cancer (GC) cells. CCK-8, plate colony formation and soft agar assays revealed that SLC35B4 is essential for survival and proliferation in GC cells and nude mice models. SLC35B4 expression is markedly higher in GC tissues compared with control noncancerous tissues. Immunohistochemistry revealed that SLC35B4 expression is positively correlated with YAP1 expression in human GC tissues, and this correlation is also confirmed in the GC TCGA data set. GC patients with high levels of SLC35B4 expression have poorer prognosis than those with low levels of SLC35B4 expression. Collectively, our findings defined SLC35B4 as an important downstream oncogenic target of YAP1, suggesting that dysregulated signaling of a novel YAP1/SLC35B4 axis promotes GC development and progression, and this axis could be a potential candidate for prognosis and therapeutics in GC.

Evolution of protein N-glycosylation process in Golgi apparatus which shapes diversity of protein N-glycan structures in plants, animals and fungi.

Protein N-glycosylation (PNG) is crucial for protein folding and enzymatic activities, and has remarkable diversity among eukaryotic species. Little is known of how unique PNG mechanisms arose and evolved in eukaryotes. Here we demonstrate a picture of onset and evolution of PNG components in Golgi apparatus that shaped diversity of eukaryotic protein N-glycan structures, with an emphasis on roles that domain emergence and combination played on PNG evolution. 23 domains were identified from 24 known PNG genes, most of which could be classified into a single clan, indicating a single evolutionary source for the majority of the genes. From 153 species, 4491 sequences containing the domains were retrieved, based on which we analyzed distribution of domains among eukaryotic species. Two domains in GnTV are restricted to specific eukaryotic domains, while 10 domains distribute not only in species where certain unique PNG reactions occur and thus genes harboring these domains are supoosed to be present, but in other ehkaryotic lineages. Notably, two domains harbored by ß-1,3 galactosyltransferase, an essential enzyme in forming plant-specific Lea structure, were present in separated genes in fungi and animals, suggesting its emergence as a result of domain shuffling.