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| 1 | Gene expression profiling and endothelin in acute experimental pancreatitis显示文摘AIM:To analyze gene expression profiles in an experimental pancreatitis and provide functional reversal of hypersensitivity with candidate gene endothelin-1 antagonists.METHODS:Dibutyltin dichloride(DBTC) is a chemical used as a polyvinyl carbonate stabilizer/catalyzer,biocide in agriculture,antifouling agent in paint and fabric.DBTC induces an acute pancreatitis flare through generation of reactive oxygen species.Lewis-inbred rats received a single i.v.injection with either DBTC or vehicle.Spinal cord and dorsal root ganglia(DRG) were taken at the peak of inflammation and processed for transcriptional profiling with a cDNA microarray biased for rat brain-specific genes.In a second study,groups of animals with DBTC-induced pancreatitis were treated with endothelin(ET) receptor antagonists [ET-A(BQ123) and ET-B BQ788)].Spontaneous pain related mechanical and thermal hypersensitivity were measured.Immunohistochemical analysis was performed using anti-ET-A and ET-B antibodies on sections from pancreatic tissues and DRG of the T10-12 spinal segments.RESULTS:Animals developed acute pancreatic inflammation persisting 7-10 d as confirmed by pathological studies(edema in parenchyma,loss of pancreatic architecture and islets,infiltration of inflammatory cells,neutrophil and mononuclear cells,degeneration,vacuolization and necrosis of acinar cells) and the painrelated behaviors(cutaneous secondary mechanical and thermal hypersensitivity).Gene expression profile was different in the spinal cord from animals with pancreatitis compared to the vehicle control group.Over 260 up-regulated and 60 down-regulated unique genes could be classified into 8 functional gene families:circulatory/acute phase/immunomodulatory;extracellular matrix;structural;channel/receptor/transporter;signaling transduction;transcription/translation-related;antioxidants/chaperones/heat shock;pancreatic and other enzymes.ET-1 was among the 52 candidate genes upregulated greater than 2-fold in animals with pancreatic inflammation and visceral pain-related behavior.Treatments with the ET-A(BQ123) and ET-B(BQ-788) antagonists revealed significant protection against inflammatory pain related mechanical and thermal hypersensitivity behaviors in animals with pancreatitis(P < 0.05).Open field spontaneous behavioral activity(at baseline,day 6 and 30 min after drug treatments(BQ123,BQ788) showed overall stable activity levels indicating that the drugs produced no undesirable effects on normal exploratory behaviors,except for a trend toward reduction of the active time and increase in resting time at the highest dose(300 μmol/L).Immunocytochemical localization revealed that expression of ET-A and ET-B receptors increased in DRG from animals with pancreatitis.Endothelin receptor localization was combined in dual staining with neuronal marker NeuN,and glia marker,glial fibrillary acidic protein.ET-A was expressed in the cell bodies and occasional nuclei of DRG neurons in na ve animals.However,phenotypic expression of ET-A receptor was greatly increased in neurons of all sizes in animals with pancreatitis.Similarly,ET-B receptor was localized in neurons and in the satellite glia,as well as in the Schwann cell glial myelin sheaths surrounding the axons passing through the DRG.CONCLUSION:Endothelin-receptor antagonists protect against inflammatory pain responses without interfering with normal exploratory behaviors.Candidate genes can serve as future biomarkers for diagnosis and/or targeted gene therapy. | Helieh S Oz Ying Lu Louis P Vera-Portocarrero Pei Ge Ada Silos-Santiago Karin N Westlund | 2012 | World Journal of Gastroenterology2012，18，32： | 6 |
| 2 | Multiorgan chronic inflammatory hepatobiliary pancreatic murine model deficient in tumor necrosis factor receptors 1 and 2显示文摘AIM: To provoke persistent/chronic multiorgan inflammatory response and to contribute to stones formation followed by fibrosis in hepatobiliary and pancreatic tissues. METHODS: Tumor necrosis factor receptors 1 and 2(TNFR1/R2) deficient mice reared in-house were given dibutyltin dichloride(DBTC) twice within 10 d by oral gavage delivery. Sham control animals received vehicle treatment and na?ve animals remained untreated throughout the study. Animals were monitored daily for symptoms of pain and discomfort. The abdominal and hindpaw hypersensitivity were assessed with von Frey microfilaments. Exploratory behaviors were recorded at the baseline, after initiation of treatment, and before study termination. Histopathological changes were examined postmortem in tissues. Collagen accumulation and fibrosis were confirmed with Sirius Red staining. RESULTS: Animals lost weight after oral administration of DBTC and developed persistent inflammatory abdominal and hindpaw hypersensitivity compared to sham-treated controls(P < 0.0001). These pain related secondary mechanical hypersensitivity responses increased more than 2-fold in DBTC-treated animals. The drastically diminished rearing and grooming rates persisted after DBTC administration throughout the study. Gross as well as micropathology at one month confirmed that animals treated with DBTC developed chronic hepatobiliary injuries evidenced with activation of stellate cells, multifocal necrosis, fatty degeneration of hepatocytes, periportal infiltration of inflammatory cells, and prominent biliary ductal dilation. The severity of hepatitis was scored 3.7 ± 0.2(severe) in DBTC-treated animals vs score 0(normal) in shamtreated animals. Fibrotic thickening was extensive around portal ducts, in hepatic parenchyma as well as in lobular pancreatic structures and confirmed with Sirius Red histopathology. In addition, pancreatic microarchitecture was presented with distortion of islets, and parenchyma, infiltration of inflammatory cells, degeneration, vacuolization, and necrosis of acinar cells and distention of pancreatic ducts. Extent of pancreatic damage and pancreatitis were scored 3.6 ± 0.4(severe) for DBTC-treated in contrast to score 0(normal) in sham-treated animals. The gall bladder became expanded with ductal distention, and occasional bile stones were detected along with microscopic hepatic lesions. DBTC-treated animals developed splenic hypertrophy with increased weight and length(P < 0.01) along with thymic atrophy(P < 0.001). Finally, colitic lesions and colitis were prominent in DBTC-treated animals and scored 3.4 ± 0.3(moderately severe) vs 0(normal) for the sham-treated animals. CONCLUSION: This is the first report of chronic inflammatory multiorgan hepatobiliary pancreatitis, along with fibrosis and calculi formation induced reliably utilizing oral DBTC administration in TNFR1/R2 deficient mice. | Helieh S Oz | 2016 | World Journal of Gastroenterology2016，22，21： | 3 |
| 3 | Comparative efficacies of 2 cysteine prodrugs and a glutathione delivery agent in a colitis model显示文摘 | Helieh S. Oz Theresa S. Chen Herbert Nagasawa | 2007 | Translational Research2007，，2： | 1 |
| 4 | Chronic inflammation and pain in a tumor necrosis factor receptor (TNFR) (p55/p75-/-) dual deficient murine model显示文摘 | Karin N. Westlund Liping Zhang Fei Ma Helieh S. Oz | 2012 | Translational Research2012，，1： | 1 |
| 5 | The green tea polyphenol-epigallocatechin-3-gallate blocks nuclear factor2-B activation by inhibiting I-B kinase activity in the intestinal epithelial cellline IEC26显示文摘 | Yang FJ Helieh SO Barve S | 2001 | Mol Pharmacol2001，60，： | 1 |
| 6 | The Green Tea Polyphenol(_) -Epigallocatechin-3-Gallate Blocks Nuclear Factor-_B Activation by Inhibiting I_B Kinase Activity in the Intestinal Epithelial Cell Line IEC-6显示文摘 | Yang FJ Helieh SO Barve S | 2001 | Mol Pharmacol2001，60，： | 1 |
| 7 | Green tea polyphenols mediated apoptosis tea polyphenols mediated apoptosis in intestinal epithelial cells intestinal epithelial cells by a FADD-dependent pathway fad-dependent pathway显示文摘 | Helieh S Jeffrey O Ebersole L | | 0，，03： | 1 |
| 8 | Lactoferrin Levels in the Gastric Tissue of Helicobacter pylori -Positive and -Negative Patients and Its Effect on Anemia显示文摘 | Ya?ar Do?an Tülay Erkan Zerrin ?nal Merve Usta Gülen Do?usoy Fügen ?ullu ?oku?ra? Tufan Kutlu Helieh S. Oz | 2012 | Mediators of Inflammation2012，，： | 1 |
| 9 | Antioxidants as novel therapy in a murine model of colitis显示文摘 | Helieh S. Oz Theresa S. Chen Craig J. McClain Willem J.S. de Villiers | 2005 | The Journal of Nutritional Biochemistry2005，，5： | 1 |
| 10 | Efficacy of a transforming growth factor beta 2 containing nutritional support formula in a murine model of inflammatory bowel disease显示文摘 | Helieh S Oz Ray M Chen T S | 2004 | Journal of the American College of Nutrition2004，23，3： | 1 |
| 11 | The green tea polyphenols - epi- gallocatechin-3-gallate blocks nuclear factor-B activation by inhibi- tion IκB kinase activity in the intestinal epithelial cell line LEC-6 显示文摘 | Yang F J Helieh SO Barve S | 2001 | Mol Phamacol2001，60，3： | 1 |
| 12 | L-Arginine and Asymmetric Dimethylarginine Are Early Predictors for Survival in Septic Patients with Acute Liver Failure显示文摘 | Thorsten Brenner Thomas H. Fleming Claudia Rosenhagen Ute Krauser Markus Mieth Thomas Bruckner Eike Martin Peter P. Nawroth Markus A. Weigand Angelika Bierhaus Stefan Hofer Helieh S. Oz | 2012 | Mediators of Inflammation2012，，： | 1 |
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