Digestive Disease Research Center

Los Angeles, CA, United States

Digestive Disease Research Center

Los Angeles, CA, United States
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Taghavi N.,Iran National Institute of Genetic Engineering and Biotechnology | Biramijamal F.,Iran National Institute of Genetic Engineering and Biotechnology | Abbaszadegan M.R.,Mashhad University of Medical Sciences | Khademi H.,Digestive Disease Research Center | And 2 more authors.
Archives of Iranian Medicine | Year: 2010

Background: The incidence of esophageal squamous cell carcinoma (ESCC) is very high in northeastern Iran. However, the genetic predisposing factors to ESCC in this region have not been clearly defined. The P21 (waf1/cip1) gene is involved in the arrest of cellular growth, as induced by the p53 tumor suppressor gene. Two polymorphisms of p21 gene in codon 31 (p21 C98A, dbSNP rs1801270) and the 3'UTR (p21 C70T, dbSNP rs1059234) may affect protein expression and play a role in cancer susceptibility. The present study aimed to investigate the association of p21 polymorphisms in codon 31 and the 3'UTR, and cigarette smoking on the risk of ESCC in northeastern Iran.Methods: A case-control study was carried out to detect the p21 polymorphism in the 3'UTR and codon 31 of samples from 126 ESCC cases and 100 controls from 2006 to 2007. There were no significant differences of age and sex between cases and controls. Genotyping of p21 polymorphisms were determined with the PCR-RFLP method. Conditional logistic regression was used to adjust for potential confounders.Results: None of the p21 genotypes were significantly associated with risk of ESCC, even after adjusting for age and gender (P=0.52, OR=1.24; 95%CI: 0.63 - 2.42). However, the presence of these polymorphisms in combination with cigarette smoking had a synergistic interaction in ESCC carcinogenesis in northeastern Iran (P=0.02, OR=8.38; 95%CI:1.03 - 67.93).Conclusions: Our data suggests that these two p21 polymorphisms, both alone and in combination, are not genetic susceptibility biomarkers for ESCC. However, their interaction with cigarette smoking may influence the susceptibility to ESCC development in northeastern Iran.


Quinn M.,Texas A&M University | Ueno Y.,Tohoku University | Pae H.Y.,Texas A&M University | Huang L.,Texas A&M University | And 12 more authors.
American Journal of Physiology - Gastrointestinal and Liver Physiology | Year: 2012

Cholestatic patients often present with clinical features suggestive of adrenal insufficiency. In the bile duct-ligated (BDL) model of cholestasis, the hypothalamic-pituitaryadrenal (HPA) axis is suppressed. The consequences of this suppression on cholangiocyte proliferation are unknown. We evaluated 1) HPA axis activity in various rat models of cholestasis and 2) effects of HPA axis modulation on cholangiocyte proliferation. Expression of regulatory molecules of the HPA axis was determined after BDL, partial BDL, and -naphthylisothiocyanate (ANIT) intoxication. The HPA axis was suppressed by inhibition of hypothalamic corticotropinreleasing hormone (CRH) expression by central administration of CRH-specific Vivo-morpholinos or by adrenalectomy. After BDL, the HPA axis was reactivated by 1) central administration of CRH, 2) systemic ACTH treatment, or 3) treatment with cortisol or corticosterone for 7 days postsurgery. There was decreased expression of 1) hypothalamic CRH, 2) pituitary ACTH, and 3) key glucocorticoid synthesis enzymes in the adrenal glands. Serum corticosterone and cortisol remained low after BDL (but not partial BDL) compared with sham surgery and after 2 wk of ANIT feeding. Experimental suppression of the HPA axis increased cholangiocyte proliferation, shown by increased cytokeratin-19- and proliferating cell nuclear antigen-positive cholangiocytes. Conversely, restoration of HPA axis activity inhibited BDL-induced cholangiocyte proliferation. Suppression of the HPA axis is an early event following BDL and induces cholangiocyte proliferation. Knowledge of the role of the HPA axis during cholestasis may lead to development of innovative treatment paradigms for chronic liver disease.


Huang L.,Texas A&M University | Huang L.,Digestive Disease Research Center | Huang L.,Sun Yat Sen University | Ramirez J.C.,Texas A&M University | And 12 more authors.
Laboratory Investigation | Year: 2011

Cholangiocarcinomas are devastating cancers of biliary origin with limited treatment options. It has previously been shown that the endocannabinoid anandamide exerts antiproliferative effects on cholangiocarcinoma independent of any known cannabinoid receptors, and by the stabilization of lipid rafts, thereby allowing the recruitment and activation of the Fas death receptor complex. Recently, GPR55 was identified as a putative cannabinoid receptor; therefore, the role of GPR55 in the antiproliferative effects of anandamide was evaluated. GPR55 is expressed in all cholangiocarcinoma cells and liver biopsy samples to a similar level as in non-malignant cholangiocytes. Treatment with either anandamide or the GPR55 agonist, O-1602, reduced cholangiocarcinoma cell proliferation in vitro and in vivo. Furthermore, knocking down the expression of GPR55 prevented the antiproliferative effects of anandamide. Coupled to these effects was an increase in JNK activity. The antiproliferative effects of anandamide could be blocked by pretreatment with a JNK inhibitor and the lipid raft disruptors Β-methylcyclodextrin and fillipin III. Activation of GPR55 by anandamide or O-1602 increased the amount of Fas in the lipid raft fractions, which could be blocked by pretreatment with the JNK inhibitor. These data represent the first evidence that GPR55 activation by anandamide can lead to the recruitment and activation of the Fas death receptor complex and that targeting GPR55 activation may be a viable option for the development of therapeutic strategies to treat cholangiocarcinoma. © 2011 USCAP, Inc All rights reserved.


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 7 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.


Dostal D.,Texas A&M University | Dostal D.,Central Texas Veterans Health Care System | Glaser S.,Central Texas Veterans Health Care System | Glaser S.,Digestive Disease Research Center | And 2 more authors.
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.


McMillin M.,Central Texas Veterans Healthcare System | McMillin M.,Texas A&M University | Frampton G.,Central Texas Veterans Healthcare System | Frampton G.,Texas A&M University | And 10 more authors.
Journal of Neurochemistry | Year: 2015

Hepatic encephalopathy (HE) is a serious neurological complication of acute and chronic liver failure. Expression of the neurosteroid/bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) has been demonstrated in the brain and is thought to be neuroprotective. However, it is unknown how TGR5 signaling can influence the progression and associated neuroinflammation of HE. HE was induced in C57Bl/6 mice via intraperitoneal injection of azoxymethane (AOM) and tissue was collected throughout disease progression. TGR5 expression was elevated in the frontal cortex following AOM injection in mice. The cellular localization of TGR5 was found in both neurons and microglia in the cortex of C57Bl/6 mice. Central infusion of the TGR5 agonist, betulinic acid, prior to AOM injection delayed neurological decline, increased cortical cyclic adenosine monophosphate concentrations, reduced microglia activation and proliferation, and reduced proinflammatory cytokine production. Betulinic acid treatment in vitro reduced the neuronal expression of chemokine ligand 2, a chemokine previously demonstrated to contribute to HE pathogenesis. Lastly, treatment of the microglia cell line EOC-20 with conditioned media from betulinic acid-treated primary neurons decreased phagocytic activity and cytokine production. Together, these data identify that activation of TGR5, which is up-regulated during HE, alleviates neuroinflammation and improves outcomes of AOM-treated mice through neuron and microglia paracrine signaling. © 2015 International Society for Neurochemistry.


PubMed | Digestive Disease Research Center, Central Texas Veterans Health Care System and Texas A&M University
Type: Journal Article | Journal: 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.


PubMed | Japan Science and Technology Agency, Scott and White Digestive Disease Research Center, Digestive Disease Research Center and Texas A&M University
Type: Journal Article | Journal: Laboratory investigation; a journal of technical methods and pathology | Year: 2014

Cholangiopathies are characterized by dysregulation of the balance between biliary growth and loss. We have shown that histamine (HA) stimulates biliary growth via autocrine mechanisms. To evaluate the paracrine effects of mast cell (MC) stabilization on biliary proliferation, sham or BDL rats were treated by IP-implanted osmotic pumps filled with saline or cromolyn sodium (24mg/kg BW/day (inhibits MC histamine release)) for 1 week. Serum, liver blocks and cholangiocytes were collected. Histidine decarboxylase (HDC) expression was measured using real-time PCR in cholangiocytes. Intrahepatic bile duct mass (IBDM) was evaluated by IHC for CK-19. MC number was determined using toluidine blue staining and correlated to IBDM. Proliferation was evaluated by PCNA expression in liver sections and purified cholangiocytes. We assessed apoptosis using real-time PCR and IHC for BAX. Expression of MC stem factor receptor, c-kit, and the proteases chymase and tryptase were measured by real-time PCR. HA levels were measured in serum by EIA. In vitro, MCs and cholangiocytes were treated with 0.1% BSA (basal) or cromolyn (25M) for up to 48h prior to assessing HDC expression, HA levels and chymase and tryptase expression. Supernatants from MCs treated with or without cromolyn were added to cholangiocytes before measuring (i) proliferation by MTT assays, (ii) HDC gene expression by real-time PCR and (iii) HA release by EIA. In vivo, cromolyn treatment decreased BDL-induced: (i) IBDM, MC number, and biliary proliferation; (ii) HDC and MC marker expression; and (iii) HA levels. Cromolyn treatment increased cholangiocyte apoptosis. In vitro, cromolyn decreased HA release and chymase and tryptase expression in MCs but not in cholangiocytes. Cromolyn-treated MC supernatants decreased biliary proliferation and HA release. These studies provide evidence that MC histamine is key to biliary proliferation and may be a therapeutic target for the treatment of cholangiopathies.


PubMed | Digestive Disease Research Center and Texas A&M University
Type: Journal Article | Journal: The American journal of pathology | Year: 2016

Hepatic encephalopathy is a serious neurological complication of liver failure. Serum bile acids are elevated after liver damage and may disrupt the blood-brain barrier and enter the brain. Our aim was to assess the role of serum bile acids in the neurological complications after acute liver failure. C57Bl/6 or cytochrome p450 7A1 knockout (Cyp7A1(-/-)) mice were fed a control, cholestyramine-containing, or bile acid-containing diet before azoxymethane (AOM)-induced acute liver failure. In parallel, mice were given an intracerebroventricular infusion of farnesoid X receptor (FXR) Vivo-morpholino before AOM injection. Liver damage, neurological decline, and molecular analyses of bile acid signaling were performed. Total bile acid levels were increased in the cortex of AOM-treated mice. Reducing serum bile acids via cholestyramine feeding or using Cyp7A1(-/-) mice reduced bile acid levels and delayed AOM-induced neurological decline, whereas cholic acid or deoxycholic acid feeding worsened AOM-induced neurological decline. The expression of bile acid signaling machinery apical sodium-dependent bile acid transporter, FXR, and small heterodimer partner increased in the frontal cortex, and blocking FXR signaling delayed AOM-induced neurological decline. In conclusion, circulating bile acids may play a pathological role during hepatic encephalopathy, although precisely how they dysregulate normal brain function is unknown. Strategies to minimize serum bile acid concentrations may reduce the severity of neurological complications associated with liver failure.


PubMed | Digestive Disease Research Center and Central Texas Veterans Health Care System
Type: | Journal: Hepatology (Baltimore, Md.) | Year: 2017

Activated mast cells (MCs) release histamine (HA) and MCs infiltrate the liver following bile duct ligation (BDL) increasing intrahepatic bile duct mass (IBDM) and fibrosis. We evaluated the effects of BDL in MC deficient mice.WT and KitBDL-induced liver damage was reduced in the BDL KitMCs promote hyperplasia, fibrosis and vascular cell activation. Knockout of MCs decreases BDL-induced damage. Modulation of MCs may be important in developing therapeutics for cholangiopathies. This article is protected by copyright. All rights reserved.

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