BackgroundPalmitic acid, the most common saturated free fatty acid, has been implicated in ER (endoplasmic reticulum) stress-mediated apoptosis. This lipoapotosis is dependent, in part, on the upregulation of the activating transcription factor-4 (ATF4). To better understand the mechanisms by which palmitate upregulates the expression level of ATF4, we integrated literature information on palmitate-induced ER stress signaling into a discrete dynamic model. The model provides an in silico framework that enables simulations and predictions. The model predictions were confirmed through further experiments in human hepatocellular carcinoma (HepG2) cells and the results were used to update the model and our current understanding of the signaling induced by palmitate.ResultsThe three key things from the in silico simulation and experimental results are: 1) palmitate induces different signaling pathways (PKR (double-stranded RNA-activated protein kinase), PERK (PKR-like ER kinase), PKA (cyclic AMP (cAMP)-dependent protein kinase A) in a time dependent-manner, 2) both ATF4 and CREB1 (cAMP-responsive element-binding protein 1) interact with the Atf4 promoter to contribute to a prolonged accumulation of ATF4, and 3) CREB1 is involved in ER-stress induced apoptosis upon palmitate treatment, by regulating ATF4 expression and possibly Ca2+ dependent-CaM (calmodulin) signaling pathway.ConclusionThe in silico model helped to delineate the essential signaling pathways in palmitate-mediated apoptosis.
Taste preference tests, with simultaneous presentation of treated and untreated food, were administered to 24 common vampire bats (Desmodus rotundus). The bats received brief exposures to four different stimuli representing sweet, salty, sour, and bitter tastes, each at four different concentrations. Despite a strong location bias, the bats significantly (P < 0.01) avoided the highest concentrations of the salty, sour, and bitter tastes. Consumption of the sweet stimulus at all concentrations was similar to that of the untreated standard. Vampires evidently can discriminate based on taste, although their ability is apparently poorly developed when compared with some euryphagous species such as the rat. Hence, taste is probably not a factor in host selection by the vampire.
The blood of beef cattle given single doses (1 milligram per kilogram of body weight) of diphenadione (2-diphenylacetyl-1,3-indandione) became toxic to vampire bats (Desmodus rotundus) and remained toxic for 3 days without harming the cattle. Cattle at three ranches in Mexico treated with single intraruminal injections of diphenadione experienced a reduction in vampire bat bites of 93 percent. Bioassays of milk and liver from cattle treated orally with diphenadione in the laboratory indicated that there were no residue problems.
Neural differentiation is largely dependent on extracellular signals within the cell microenvironment. These extracellular signals are mainly in the form of soluble factors that activate intracellular signaling cascades that drive changes in the cell nucleus. However, it is becoming increasingly apparent that the physical microenvironment provides signals that can also influence lineage commitment and very low modulus surfaces has been repeatedly demonstrated to promote neurogenesis. The molecular mechanisms governing mechano-induced neural differentiation are still largely uncharacterized; however, a growing body of evidence indicates that physical stimuli can regulate known signaling cascades and transcription factors involved in neural differentiation. Understanding how the physical environment affects neural differentiation at the molecular level will enable research and design of materials that will eventually enhance neural stem cell (NSC) differentiation, homogeneity and specificity.
Neural differentiation of mesenchymal stem cells is a controversial phenomenon, as it would require transdifferentiation across the mesoderm-ectoderm barrier. However, several laboratories have observed that MSCs are able to be induced to express neural characteristics. Previously, we demonstrated that the cAMP-elevating agents, forskolin and IBMX, induced neural-like differentiation of MSCs, including expression of neural markers and increased sensitivity to neurotransmitters. However, due to the broad range of effects that forskolin and IBMX can elicit through the intracellular second messenger, cAMP, a better mechanistic understanding is required. Here, we show that neural induction by forskolin and IBMX is dependent on downregulation of expression of the master transcriptional regulator, neuron restrictive silencer factor (NRSF), and its downstream target genes. Since silencing of NRSF is known to initiate neural differentiation, it suggests that forskolin and IBMX result in transdifferentiation of MSCs into a neural lineage.
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