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Dostal D.,Texas A&M University | Glaser S.,Central Texas Veterans Health Care System | Glaser S.,Digestive Disease Research Center | Baudino T.A.,Texas A&M University
Comprehensive Physiology | Year: 2015

Cardiac function is mediated by interactions between the cellular constituents of the heart, as well as the extracellular matrix. The major cell types of the heart include cardiac fibroblasts, myocytes, endothelial cells, and vascular smooth muscle cells. In addition, there are also resident stem cells and transient cell types, such as immune cells. Interactions in the heart include chemical, mechanical, and electrical signals, which vary depending on the developmental stage, disease state, and specific cell type. Understanding how these different signals interact at the molecular, cellular, and organ levels is important for better understanding cardiac function under a variety of physiological and pathological conditions. Cardiac fibroblasts play key roles in maintaining normal cardiac form and function, as well as in the cardiac remodeling process during pathological conditions, such as myocardial infarction and hypertension. Regardless of normal or pathological status of the heart, fibroblasts have multiple functions, such as synthesis and deposition of extracellular matrix and cell-cell communication with other cardiac cells, including myocytes and endothelial cells. Interactions with other cell types can affect multiple cell signaling pathways (e.g., ERK, JNK, and p38), the expression and secretion of numerous growth factors and cytokines, microRNA exchange, gene and protein expression, and angiogenesis. In this review, we provide insight into the cardiac fibroblast under normal and pathological conditions to illustrate their importance in maintaining proper cardiac function. © 2015 American Physiological Society. Source

Quinn M.,Texas A&M University | McMillin M.,Texas A&M University | Galindo C.,Texas A&M University | Frampton G.,Texas A&M University | And 3 more authors.
Digestive and Liver Disease | Year: 2014

Background: The blood brain barrier tightly regulates the passage of molecules into the brain and becomes leaky following obstructive cholestasis. The aim of this study was to determine if increased serum bile acids observed during cholestasis permeabilize the blood brain barrier. Methods: Rats underwent bile duct ligation or deoxycholic or chenodeoxycholic acid injections and blood brain barrier permeability assessed. In vitro, the permeability of rat brain microvessel endothelial cell monolayers, the expression and phosphorylation of occludin, ZO-1 and ZO-2 as well as the activity of Rac1 was assessed after treatment with plasma from cholestatic rats, or bile acid treatment, in the presence of a Rac1 inhibitor. Results: Blood brain barrier permeability was increased in vivo and in vitro following bile duct ligation or treatment with bile acids. Associated with the bile acid-stimulated increase in endothelial cell monolayer permeability was elevated Rac1 activity and increased phosphorylation of occludin. Pretreatment of endothelial cell monolayers with a Rac1 inhibitor prevented the effects of bile acid treatment on occludin phosphorylation and monolayer permeability. Conclusions: These data suggest that increased circulating serum bile acids may contribute to the increased permeability of the blood brain barrier seen during obstructive cholestasis via disruption of tight junctions. © 2014 Editrice Gastroenterologica Italiana S.r.l. Source

McMillin M.,Texas A&M University | Galindo C.,Texas A&M University | Pae H.Y.,Texas A&M University | Frampton G.,Texas A&M University | And 5 more authors.
Journal of Hepatology | Year: 2014

Background & Aims Hepatic encephalopathy (HE) is a neurologic disorder that develops during liver failure. Few studies exist investigating systemic-central signalling during HE outside of inflammatory signalling. The transcription factor Gli1, which can be modulated by hedgehog signalling or transforming growth factor β1 (TGFβ1) signalling, has been shown to be protective in various neuropathies. We measured Gli1 expression in brain tissues from mice and evaluated how circulating TGFβ1 and canonical hedgehog signalling regulate its activation. Methods Mice were injected with azoxymethane (AOM) to induce liver failure and HE in the presence of Gli1 vivo-morpholinos, the hedgehog inhibitor cyclopamine, Smoothened vivo-morpholinos, a Smoothened agonist, or TGFβ-neutralizing antibodies. Molecular analyses were used to assess Gli1, hedgehog signalling, and TGFβ1 signalling in the liver and brain of AOM mice and HE patients. Results Gli1 expression was increased in brains of AOM mice and in HE patients. Intra-cortical infusion of Gli1 vivo-morpholinos exacerbated the neurologic deficits of AOM mice. Measures to modulate hedgehog signalling had no effect on HE neurological decline. Levels of TGFβ1 increased in the liver and serum of mice following AOM administration. TGFβ neutralizing antibodies slowed neurologic decline following AOM administration without significantly affecting liver damage. TGFβ1 inhibited Gli1 expression via a SMAD3-dependent mechanism. Conversely, inhibiting TGFβ1 increased Gli1 expression. Conclusions Cortical activation of Gli1 protects mice from induction of HE. TGFβ1 suppresses Gli1 in neurons via SMAD3 and promotes the neurologic decline. Strategies to activate Gli1 or inhibit TGFβ1 signalling might be developed to treat patients with HE. © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Source

Frampton G.,Texas A&M University | Coufal M.,Texas A&M University | Li H.,Texas A&M University | Li H.,Sun Yat Sen University | And 3 more authors.
Experimental Cell Research | Year: 2010

The endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2-AG) have opposing effects on cholangiocarcinoma growth. Implicated in cancer, Notch signaling requires the γ-secretase complex for activation. The aims of this study were to determine if the opposing effects of endocannabinoids depend on the differential activation of the Notch receptors and to demonstrate that the differential activation of these receptors are due to presenilin 1 containing- and presenilin 2 containing-γ-secretase complexes. Mz-ChA-1 cells were treated with AEA or 2-AG. Notch receptor expression, activation, and nuclear translocation were determined. Specific roles for Notch 1 and 2 on cannabinoid-induced effects were determined by transient transfection of Notch 1 or 2 shRNA vectors before stimulation with AEA or 2-AG. Expression of presenilin 1 and 2 was determined after AEA or 2-AG treatment, and the involvement of presenilin 1 and 2 in the cannabinoid-induced effects was demonstrated in cell lines with low presenilin 1 or 2 expression. Antiproliferative effects of AEA required increased Notch 1 mRNA, activation, and nuclear translocation, whereas the growth-promoting effects induced by 2-AG required increased Notch 2 mRNA expression, activation, and nuclear translocation. AEA increased presenilin 1 expression and recruitment into the γ-secretase complex, whereas 2-AG increased expression and recruitment of presenilin 2. The development of novel therapeutic strategies aimed at modulating the endocannabinoid system or mimicking the mode of action of AEA on Notch signaling pathways would prove beneficial for cholangiocarcinoma management. © 2010 Elsevier Inc. Source

Leyva-Illades D.,Digestive Disease Research Center | Leyva-Illades D.,Research Service | DeMorrow S.,Digestive Disease Research Center | DeMorrow S.,Research Service
Cancer Management and Research | Year: 2013

G protein-coupled receptors (GPCRs) modulate a vast array of cellular processes. The current review gives an overview of the general characteristics of GPCRs and their role in physiological conditions. In addition, it describes the current knowledge of the physiological and pathophysiological functions of GPR55, an orphan GPCR, and how it can be exploited as a therapeutic target to combat various cancers. © Leyva-Illades and DeMorrow, publisher and licensee Dove Medical Press Ltd. Source

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