Calcium Signaling, Calcineurin and NFAT3 Molecular Pathway in Reprogramming of Fetal Gene (BNP) Expression in Cardiac Hypertrophy and Inhibitors of Cardiac Hypertrophy-Review

G-Protein Coupled Receptor (GPCR) plays a major role in cardiac hypertrophy. Isoproterenol is an agonist which binds to GPCR. This results in the activation of GS subunit. Activated Gs subunit stimulates cAMP mediated pathway. This activates the calcium signaling and elevates the calcium level. Increased calcium activates the phosphatase activity of calcineurin. Activated calcineurin dephosphorylates NFAT in cytoplasm. Dephosphorylated NFAT translocates to nucleus and binds to target region in DNA and activates re-expression of fetal genes in synergy with GATA-4 trascription factor. Reprogramming of fetal genes by NFAT- 3 and GATA-4 results in cardiac hypertrophy. Calcineurin inhibitors and rephosphorylation of NFAT can prevent cardiac hypertrophy.

Disrupting the Molecular Pathway in Myotonic Dystrophy

Myotonic dystrophy is the most common muscular dystrophy in adults. It consists of two forms: type 1 (DM1) and type 2 (DM2). DM1 is associated with a trinucleotide repeat expansion mutation, which is transcribed but not translated into protein. The mutant RNA remains in the nucleus, which leads to a series of downstream abnormalities. DM1 is widely considered to be an RNA-based disorder. Thus, we consider three areas of the RNA pathway that may offer targeting opportunities to disrupt the production, stability, and degradation of the mutant RNA.

Quantitative Acetylomics Revealed Acetylation-Mediated Molecular Pathway Network Changes in Human Nonfunctional Pituitary Neuroendocrine Tumors

Acetylation at lysine residue in a protein mediates multiple cellular biological processes, including tumorigenesis. This study aimed to investigate the acetylated protein profile alterations and acetylation-mediated molecular pathway changes in human nonfunctional pituitary neuroendocrine tumors (NF-PitNETs). The anti-acetyl antibody-based label-free quantitative proteomics was used to analyze the acetylomes between NF-PitNETs (n = 4) and control pituitaries (n = 4). A total of 296 acetylated proteins with 517 acetylation sites was identified, and the majority of which were significantly down-acetylated in NF-PitNETs (p<0.05 or only be quantified in NF-PitNETs/controls). These acetylated proteins widely functioned in cellular biological processes and signaling pathways, including metabolism, translation, cell adhesion, and oxidative stress. The randomly selected acetylated phosphoglycerate kinase 1 (PGK1), which is involved in glycolysis and amino acid biosynthesis, was further confirmed with immunoprecipitation and western blot in NF-PitNETs and control pituitaries. Among these acetylated proteins, 15 lysine residues within 14 proteins were down-acetylated and simultaneously up-ubiquitinated in NF-PitNETs to demonstrate a direct competition relationship between acetylation and ubiquitination. Moreover, the potential effect of protein acetylation alterations on NF-PitNETs invasiveness was investigated. Overlapping analysis between acetylomics data in NF-PitNETs and transcriptomics data in invasive NF-PitNETs identified 26 overlapped molecules. These overlapped molecules were mainly involved in metabolism-associated pathways, which means that acetylation-mediated metabolic reprogramming might be the molecular mechanism to affect NF-PitNET invasiveness. This study provided the first acetylomic profiling and acetylation-mediated molecular pathways in human NF-PitNETs, and offered new clues to elucidate the biological functions of protein acetylation in NF-PitNETs and discover novel biomarkers for early diagnosis and targeted therapy of NF-PitNETs.

Suicide Related Phenotypes in a Bipolar Sample: Genetic Underpinnings

Suicide in Bipolar Disorder (BD) is a relevant clinical concern. Genetics may shape the individual risk for suicide behavior in BD, together with known clinical factors. The lack of consistent replication in BD may be associated with its multigenetic component. In the present contribution we analyzed a sample of BD individuals (from STEP-BD database) to identify the genetic variants potentially associated with three different suicide-related phenotypes: 1) a feeling that the life was not worth living; 2) fantasies about committing a violent suicide; 3) previous attempted suicide. The sample under analysis included 1115 BD individuals. None of the SNPs reached genome-wide significance. However, a trend of association was evidenced for rs2767403, an intron variant of AOPEP gene, in association with phenotype #1 (p = 5.977 × 10−6). The molecular pathway analysis showed a significant enrichment in all the investigated phenotypes on pathways related to post synaptic signaling, neurotransmission and neurodevelopment. Further, NOTCH signaling or the γ-aminobutyric acid (GABA) -ergic signaling were found to be associated with specific suicide-related phenotypes. The present investigation contributes to the hypothesis that the genetic architecture of suicide behaviors in BD is related to alteration of entire pathways rather than single genes. In particular, our molecular pathway analysis points on some specific molecular events that could be the focus of further research in this field.

SNHG6/mir-26a-5p/PIM1 Axis Could Regulate Tumorigenic Glioma Cells Behaviors

Purpose Today, long non-coding RNAs (lncRNAs) are considered more than before. SNHG6 like many lncRNAs is proved to have different roles in human malignancies such as hepatocellular carcinoma, brain cancers and … . Glioma with a poor prognosis needs a faster way to prognosticate. Finding key molecular mechanisms of gliomagenesis is essential for producing effective drugs. We indicated a new possible molecular gliomagenesis pathway involving of PIM1 and mir-26a-5p. Methods SNHG6 expression level was assessed in 29 brain tumor samples. Two specific siRNAs were designed and SNHG6 was silenced in A172 & U87-MG cells. Cell cycle progression, apoptosis, EMT, migration ability and survival of target cells were assessed following of SNHG6 knock-down. Results Expression of SNHG6 in glioma tissues and target cell lines was satisfied. Following of using siRNAs, G1 arrest, mesenchymal characteristics reduction and much apoptosis of U87-MG tumorigenic cells was proved. Target cells demonstrated less proliferation and survival ability when SNHG6 was silenced. Following of SNHG6 knockdown, mir-26a-5p and PIM1 mRNA were fluctuated and U87-MG cells showed this phenomenon more prominent. Conclusion In this research we indicated a new possible molecular pathway that could affect gliomagenesis. SNHG6/mir-26a-5p/PIM1 might be an unknown gliomagenesis molecular pathway for new treatments.

Algorithmically Deduced FREM2 Molecular Pathway Is a Potent Grade and Survival Biomarker of Human Gliomas

Gliomas are the most common malignant brain tumors with high mortality rates. Recently we showed that the FREM2 gene has a role in glioblastoma progression. Here we reconstructed the FREM2 molecular pathway using the human interactome model. We assessed the biomarker capacity of FREM2 expression and its pathway as the overall survival (OS) and progression-free survival (PFS) biomarkers. To this end, we used three literature and one experimental RNA sequencing datasets collectively covering 566 glioblastomas (GBM) and 1097 low-grade gliomas (LGG). The activation level of deduced FREM2 pathway showed strong biomarker characteristics and significantly outperformed the FREM2 expression level itself. For all relevant datasets, it could robustly discriminate GBM and LGG (p < 1.63 × 10−13, AUC > 0.74). High FREM2 pathway activation level was associated with poor OS in LGG (p < 0.001), and low PFS in LGG (p < 0.001) and GBM (p < 0.05). FREM2 pathway activation level was poor prognosis biomarker for OS (p < 0.05) and PFS (p < 0.05) in LGG with IDH mutation, for PFS in LGG with wild type IDH (p < 0.001) and mutant IDH with 1p/19q codeletion(p < 0.05), in GBM with unmethylated MGMT (p < 0.05), and in GBM with wild type IDH (p < 0.05). Thus, we conclude that the activation level of the FREM2 pathway is a potent new-generation diagnostic and prognostic biomarker for multiple molecular subtypes of GBM and LGG.