Search results for "RACE"

Evaluating the antifibrotic potency of galunisertib in a human ex vivo model of liver fibrosis

2017

Background and Purpose Liver fibrosis is a major cause of liver-related mortality and, so far, no effective antifibrotic drug is available. Galunisertib, a TGF-β receptor type I kinase inhibitor, is a potential candidate for the treatment of liver fibrosis. Here, we evaluated the potency of galunisertib in a human ex vivo model of liver fibrosis. Experimental Approach Antifibrotic potency and associated mechanisms were studied ex vivo, using both healthy and cirrhotic human precision-cut liver slices. Fibrosis-related parameters, both transcriptional and translational level, were assessed after treatment with galunisertib. Key Results Galunisertib showed a prominent antifibrotic potency. Ph…

MicroRNA Intercellular Transfer and Bioelectrical Regulation of Model Multicellular Ensembles by the Gap Junction Connectivity.

2017

We have studied theoretically the microRNA (miRNA) intercellular transfer through voltage-gated gap junctions in terms of a biophysically grounded system of coupled differential equations. Instead of modeling a specific system, we use a general approach describing the interplay between the genetic mechanisms and the single-cell electric potentials. The dynamics of the multicellular ensemble are simulated under different conditions including spatially inhomogeneous transcription rates and local intercellular transfer of miRNAs. These processes result in spatiotemporal changes of miRNA, mRNA, and ion channel protein concentrations that eventually modify the bioelectrical states of small multi…

Silencing of C3G increases cardiomyocyte survival inhibition and apoptosis via regulation of p-ERK1/2 and Bax.

2018

Experimental studies have shown that overexpression of Rap guanine nucleotide exchange factor 1 (C3G) plays pro-survival and anti-apoptotic roles through molecule phosphorylated extracellular signal-regulated kinase1/2 (p-ERK1/2) in cardiomyocytes. However, it is still unclear if silencing of C3G may increase cell survival inhibition and apoptosis in cardiomyocytes, and whether C3G silence induced injuries are reduced by the overexpression of C3G through regulation of p-ERK1/2 and pro-apoptotic molecule Bax. In this study, the rat-derived H9C2 cardiomyocytes were infected with C3G small hairpin RNA interference recombinant lentiviruses, which silenced the endogenous C3G expression in the ca…

2020

Physical exercise induces acute physiological changes leading to enhanced tissue cross-talk and a liberation of extracellular vesicles (EVs) into the circulation. EVs are cell-derived membranous entities which carry bioactive material, such as proteins and RNA species, and are important mediators of cell-cell-communication. Different types of physical exercise interventions trigger the release of diverse EV subpopulations, which are hypothesized to be involved in physiological adaptation processes leading to health benefits and longevity. Large EVs (“microvesicles” and “microparticles”) are studied frequently in the context of physical exercise using straight forward flow cytometry approach…

Comparative Proteomics Unveils LRRFIP1 as a New Player in the DAPK1 Interactome of Neurons Exposed to Oxygen and Glucose Deprivation

2020

Altres ajuts: The group has received funding from 'la Caixa Foundation' CI15-00009, from the European Institute of Innovation and Technology (EIT) PoC-2016-SPAIN-04, which receives support from the European Union's Horizon 2020 research and innovation program, and from the 'Fundación para la Innovación y la Prospectiva en Salud en España (FIPSE)' program 3594-18. Death-associated protein kinase 1 (DAPK1) is a pleiotropic hub of a number of networked distributed intracellular processes. Among them, DAPK1 is known to interact with the excitotoxicity driver NMDA receptor (NMDAR), and in sudden pathophysiological conditions of the brain, e.g., stroke, several lines of evidence link DAPK1 with t…

Niemann-Pick type C2 protein supplementation in experimental non-alcoholic fatty liver disease

2017

BACKGROUND AND AIMS: Hepatic cholesterol deposition drives inflammation and fibrosis in non-alcoholic steatohepatitis (NASH). The Niemann-Pick type C2 (NPC2) protein plays an important role in regulating intracellular cholesterol trafficking and homeostasis. We hypothesized that intravenous NPC2 supplementation reduces cholesterol accumulation, hepatic inflammation and fibrogenesis in a nutritional NASH rat model.METHODS: Rats were fed a high-fat, high-cholesterol (HFHC) diet for four weeks resulting in moderately severe NASH. Animals were treated with intravenous NPC2 or placebo twice weekly for either the last two weeks or the entire four weeks. End-points were liver/body- and spleen/body…

Oxidative Stress: A Unifying Mechanism for Cell Damage Induced by Noise, (Water-Pipe) Smoking, and Emotional Stress-Therapeutic Strategies Targeting …

2018

Modern technologies have eased our lives but these conveniences can impact our lifestyles in destructive ways. Noise pollution, mental stresses, and smoking (as a stress-relieving solution) are some environmental hazards that affect our well-being and healthcare budgets. Scrutinizing their pathophysiology could lead to solutions to reduce their harmful effects. Recent Advances: Oxidative stress plays an important role in initiating local and systemic inflammation after noise pollution, mental stress, and smoking. Lipid peroxidation and release of lysolipid by-products, disturbance in activation and function of nuclear factor erythroid 2-related factor 2 (Nrf2), induction of stress hormones …

Intracellular ion signaling influences myelin basic protein synthesis in oligodendrocyte precursor cells

2016

Myelination in the central nervous system depends on axon-oligodendrocyte precursor cell (OPC) interaction. We suggest that myelin synthesis may be influenced by [Na+]i and [Ca2+]i signaling in OPCs. Experiments were performed in mouse cultured OPCs at day in vitro (DIV) 2-6 or acute slices of the corpus callosum at postnatal days (P) 10-30. Synthesis of Myelin Basic Protein (MBP), an "executive molecule of myelin", was used as readout of myelination. Immunohistological data revealed that MBP synthesis in cultured OPCs starts around DIV4. Transient elevations of resting [Ca2+]i and [Na+]i levels were observed in the same temporal window (DIV4-5). At DIV4, but not at DIV2, both extracellular…

Chemical probes to potently and selectively inhibit endocannabinoid cellular reuptake

2017

The extracellular effects of the endocannabinoids anandamide and 2-arachidonoyl glycerol are terminated by enzymatic hydrolysis after crossing cellular membranes by facilitated diffusion. The lack of potent and selective inhibitors for endocannabinoid transport has prevented the molecular characterization of this process, thus hindering its biochemical investigation and pharmacological exploitation. Here, we report the design, chemical synthesis, and biological profiling of natural product-derived N-substituted 2,4-dodecadienamides as a selective endocannabinoid uptake inhibitor. The highly potent (IC50 = 10 nM) inhibitor N-(3,4-dimethoxyphenyl)ethyl amide (WOBE437) exerted pronounced canna…

Autophagy as a defense strategy against stress: focus on Paracentrotus lividus sea urchin embryos exposed to cadmium

2015

Autophagy is used by organisms as a defense strategy to face environmental stress. This mechanism has been described as one of the most important intracellular pathways responsible for the degradation and recycling of proteins and organelles. It can act as a cell survival mechanism if the cellular damage is not too extensive or as a cell death mechanism if the damage/stress is irreversible; in the latter case, it can operate as an independent pathway or together with the apoptotic one. In this review, we discuss the autophagic process activated in several aquatic organisms exposed to different types of environmental stressors, focusing on the sea urchin embryo, a suitable system recently in…