Probing the epigenetic signatures in subjects with coronary artery disease

Depletion of S-adenosyl methionine and 5-methyltetrahydrofolate; and elevation of total plasma homocysteine were documented in CAD patients, which might modulate the gene-specific methylation status and alter their expression. In this study, we have aimed to delineate CAD-specific epigenetic signatures by investigating the methylation and expression of 11 candidate genes i.e. ABCG1, LIPC, PLTP, IL-6, TNF-α, CDKN2A, CDKN2B, F2RL3, FGF2, P66 and TGFBR3. The methylation-specific PCR and qRT-PCR were used to assess the methylation status and the expression of candidate genes, respectively. CAD patients showed the upregulation of IL-6, TNF-α, CDKN2A, CDKN2B, F2RL3, FGF2, P66, and TGFBR3. Hypomethylation of CDKN2A loci was shown to increase risk for CAD by 1.79-folds (95% CI 1.22–2.63). Classification and regression tree (CART) model of gene expression showed increased risk for CAD with F2RL3?>?3.4-fold, while demonstrating risk reduction with F2RL3?<?3.4-fold and IL-6?<?7.7-folds. This CAD prediction model showed the excellent sensitivity (0.98, 95% CI 0.88–1.00), specificity (0.91, 95% CI 0.86–0.92), positive predictive value (0.82, 95% CI 0.75–0.84), and negative predictive value (0.99, 95% CI 0.94–1.00) with an overall accuracy of 92.8% (95% CI 87.0–94.1%). Folate and B₁₂ deficiencies were observed in CAD cases, which were shown to contribute to hypomethylation and upregulation of the prime candidate genes i.e. CDKN2A and F2RL3. Early onset diabetes was associated with IL-6 and TNF-α hypomethylation and upregulation of CDKN2A. The expression of F2RL3 and IL-6 (or) hypomethylation status at CDKN2A locus are potential biomarkers in CAD risk prediction. Early epigenetic imprints of CAD were observed in early onset diabetes. Folate and B₁₂ deficiencies are the contributing factors to these changes in CAD-specific epigenetic signatures.

     

CDPK-mediated signalling pathways: specificity and cross-talk

Plants are constantly exposed to environmental changes and have to integrate a variety of biotic and abiotic stress stimuli. Calcium-dependent protein kinases (CDPKs) are implicated as important sensors of Ca2+ flux in plants in response to these stresses. CDPKs are encoded by multigene families, and expression levels of these genes are spatially and temporally controlled throughout development. In addition, a subset of CDPK genes responds to external stimuli. Biochemical evidence supports the idea that CDPKs are involved in signal transduction during stress conditions. Furthermore, loss-of-function and gain-of-function studies revealed that signalling pathways leading to cold, salt, drought or pathogen resistance are mediated by specific CDPK isoforms     

Stem cells: cross-talk and developmental programs

The thesis advanced in this essay is that stem cells-particularly those in the nervous system-are components in a series of inborn 'programs' that not only ensure normal development, but persist throughout life so as to maintain homeostasis in the face of perturbations-both small and great. These programs encode what has come to be called 'plasticity'. The stem cell is one of the repositories of this plasticity. This review examines the evidence that interaction between the neural stem cell (as a prototypical somatic stem cell) and the developing or injured brain is a dynamic, complex, ongoing reciprocal set of interactions where both entities are constantly in flux. We suggest that this interaction can be viewed almost from a 'systems biology' vantage point. We further advance the notion that clones of exogenous stem cells in transplantation paradigms may not only be viewed for their therapeutic potential, but also as biological tools for 'interrogating' the normal or abnormal central nervous system environment, indicating what salient cues (among the many present) are actually guiding the expression of these 'programs'; in other words, using the stem cell as a 'reporter cell'. Based on this type of analysis, we suggest some of the relevant molecular pathways responsible for this 'cross-talk' which, in turn, lead to proliferation, migration, cell genesis, trophic support, protection, guidance, detoxification, rescue, etc. This type of developmental insight, we propose, is required for the development of therapeutic strategies for neurodegenerative disease and other nervous system afflictions in humans. Understanding the relevant molecular pathways of stem cell repair phenotype should be a priority, in our view, for the entire stem cell field.     

Olfactory transduction: cross-talk between second-messenger systems

Chemosensory cilia of olfactory receptor neurons contain an adenylate cyclase which is stimulated by high concentrations of odorants. Cyclic AMP produced by this enzyme has been proposed to act as second messenger in olfactory transduction. Here we report that olfactory cilia contain calmodulin and that calmodulin potently activates olfactory adenylate cyclase by a mechanism additive to and independent from direct stimulation by odorants. Activation by calmodulin is calcium dependent and enhanced by GTP. Thus, olfactory transduction may involve a second-messenger cascade in which an odorant-induced increase in intracellular calcium concentration leads to activation of adenylate cyclase by calmodulin.     

Fimbriae-mediated host-pathogen cross-talk

Recent studies show that the coupling of fimbrial adhesins of uropathogenic Escherichia coli and pathogenic Neisseria species to their complementary receptors on host cells is a dynamic event, involving specific signaling to the bacteria as well as to the host cell. These studies have unveiled intriguing and novel mechanisms by which bacteria utilize their fimbriae to promote virulence at the mucosal surface and in deeper tissue.     

Abiotic stress signalling pathways: specificity and cross-talk

Plants exhibit a variety of responses to abiotic stresses that enable them to tolerate and survive adverse conditions. As we learn more about the signalling pathways leading to these responses, it is becoming clear that they constitute a network that is interconnected at many levels. In this article, we discuss the 'cross-talk' between different signalling pathways and question whether there are any truly specific abiotic stress signalling responses.     

Chloroplast-mitochondria cross-talk in diatoms

Diatoms are unicellular, mainly photosynthetic, eukaryotes living within elaborate silicified cell walls and believed to be responsible for around 40% of global primary productivity in the oceans. Their abundance in aquatic ecosystems is such that they have on different occasions been described as the insects, the weeds, or the cancer cells of the ocean. In contrast to higher plants and green algae which derive from a primary endosymbiosis, diatoms are now believed to originate from a serial secondary endosymbiosis involving both green and red algae and a heterotrophic exosymbiont host. As a consequence of their dynamic evolutionary history, they appear to have red algal-derived chloroplasts empowered largely by green algal proteins, working alongside mitochondria derived from the non-photosynthetic exosymbiont. This review will discuss the evidence for such an unusual assemblage of organelles in diatoms, and will present the evidence implying that it has enabled them with unorthodox metabolisms that may have contributed to their profound ecological success.     

Histone and chromatin cross-talk

Chromatin is the physiologically relevant substrate for all genetic processes inside the nuclei of eukaryotic cells. Dynamic changes in the local and global organization of chromatin are emerging as key regulators of genomic function. Indeed, a multitude of signals from outside and inside the cell converges on this gigantic signaling platform. Numerous post-translational modifications of histones, the main protein components of chromatin, have been documented and analyzed in detail. These 'marks' appear to crucially mediate the functional activity of the genome in response to upstream signaling pathways. Different layers of cross-talk between several components of this complex regulatory system are emerging, and these epigenetic circuits are the focus of this review.     

Evidence for cross-talk between stanniocalcins

There are 2 forms of stanniocalcin (STC) produced by the STC-1 gene; a 50 kDa polypeptide known as STC50 and a recently discovered group of higher molecular weight variants that are collectively referred to as big STC. Both have different tissue patterns of expression and different intracellular targeting pathways. STC50 functions locally in tissues such as muscle, liver, and kidney and is targeted to mitochondria. Big STC, on the other hand, is made by the ovaries. It signals both locally on nearby corpus luteal cells and systemically. Interestingly, however, receptor binding assays employing STC50 as the tracer have shown that the smaller ligand can bind equally to tissue receptors targeted by either form of the hormone. This suggests there may be cross-talk between ligands. The present study provides credence to this notion by demonstrating how the 2 hormones can compete for tissue receptors normally targeted by 1 form of the hormone (big STC). The results also reveal how STC50 can completely block the inhibitory effects of big STC on luteal cell progesterone release when added simultaneously. The findings therefore add credence to the possibility that there may be circumstances during which the 2 ligands functionally antagonize each other's actions.     

Tumor necrosis factor receptor cross-talk

Extensive research has been performed to unravel the mechanistic signaling pathways mediated by tumor necrosis factor receptor 1 (TNFR1), by contrast there is limited knowledge on cellular signaling upon activation of TNFR2. Recently published data have revealed that these two receptors not only function independently, but also can influence each other via cross-talk between the different signaling pathways initiated by TNFR1 and TNFR2 stimulation. Furthermore, the complexity of this cross-talk is also dependent on the different signaling kinetics between TNFR1 and TNFR2, by which a delicate balance between cell survival and apoptosis can be maintained. Some known signaling factors and the kinetics that are involved in the receptor cross-talk between TNFR1 and TNFR2 are the topic of this review.     

Idiopathic pulmonary fibrosis: an epithelial/fibroblastic cross-talk disorder

Idiopathic pulmonary fibrosis is a chronic and usually progressive lung disorder of unknown etiology. A growing body of evidence suggests that, in contrast to other interstitial lung diseases, IPF is a distinct entity in which inflammation is a secondary and non-relevant pathogenic partner. Evidence includes the presence of similar mild/moderate inflammation either in early or late disease, and the lack of response to potent anti-inflammatory therapy. Additionally, it is clear from experimental models and some human diseases that it is possible to have fibrosis without inflammation. An evolving hypothesis proposes that IPF may result from epithelial micro-injuries and abnormal wound healing.