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1.  Altered expression of P2X3 in vagal and spinal afferents following esophagitis in rats 
Histochemistry and cell biology  2009;132(6):585-597.
Purinergic P2X3 receptors are predominantly expressed in small diameter primary afferent neurons and activation of these receptors by adenosine triphosphate is reported to play an important role in nociceptive signaling. The objective of this study was to investigate the expression of P2X3 receptors in spinal and vagal sensory neurons and esophageal tissues following esophagitis in rats. Two groups of rats were used including 7 days fundus-ligated (7D-ligated) esophagitis and sham-operated controls. Esophagitis was produced by ligating the fundus and partial obstruction of pylorus that initiated reflux of gastric contents. The sham-operated rats underwent midline incision without surgical manipulation of the stomach. Expressions of P2X3 receptors in thoracic dorsal root ganglia (DRGs), nodose ganglia (NGs), and esophageal tissues were evaluated by RT–PCR, western blot and immunohistochemistry. Esophageal neurons were identified by retrograde transport of Fast Blue from the esophagus. There were no significant differences in P2X3 mRNA expressions in DRGs (T1–T3) and NGs between 7D-ligated and sham-operated rats. However, there was an upregulation of P2X3 mRNA in DRGs (T6–T12) and in the esophageal muscle. At protein level, P2X3 exhibited significant upregulation both in DRGs and in NGs of rats having chronic esophagitis. Immunohistochemical analysis exhibited a significant increase in P2X3 and TRPV1 co-expression in DRGs and NGs in 7D-ligated rats compared to sham-operated rats. The present findings suggest that chronic esophagitis results in upregulation of P2X3 and its co-localization with TRPV1 receptor in vagal and spinal afferents. Changes in P2X3 expression in vagal and spinal sensory neurons may contribute to esophageal hypersensitivity following acid reflux-induced esophagitis.
doi:10.1007/s00418-009-0639-4
PMCID: PMC4820021  PMID: 19784665
P2X3 receptor; Dorsal root ganglia; Vagus; Acid reflux; Esophagitis
2.  Anti inflammatory and anti angiogenic effect of black raspberry extract on human esophageal and intestinal microvascular endothelial cells 
Microvascular research  2014;97:167-180.
Polyphenolic compounds (anthocyanins, flavonoid glycosides) in berries prevent the initiation, promotion, and progression of carcinogenesis in rat’s digestive tract and esophagus, in part, via anti-inflammatory pathways. Angiogenesis has been implicated in the pathogenesis of chronic inflammation and tumorigenesis. In this study, we investigated the anti-inflammatory and anti-angiogenic effects of black raspberry extract (BRE) on two organ specific primary human intestinal microvascular endothelial cells, (HIMEC) and human esophageal microvascular endothelial cells (HEMEC), isolated from surgically resected human intestinal and donor discarded esophagus, respectively.
HEMEC and HIMEC were stimulated with TNF-α/IL-1β with or without BRE. The anti-inflammatory effects of BRE were assessed based upon COX-2, ICAM-1 and VCAM-1 gene and protein expression, PGE2 production, NFκB p65 subunit nuclear translocation as well as endothelial-leukocyte adhesion. The anti-angiogenic effects of BRE were assessed on cell migration, proliferation and tube formation following VEGF stimulation as well as on activation of Akt, MAPK and JNK signaling pathways.
BRE inhibited TNF-α/IL-1β-induced NFκB p65 nuclear translocation, PGE2 production, up-regulation of COX-2, ICAM-1 and VCAM-1 gene and protein expression and leukocyte binding in HEMEC but not in HIMEC. BRE attenuated VEGF-induced cell migration, proliferation and tube formation in both HEMEC and HIMEC. The anti-angiogenic effect of BRE is mediated by inhibition of Akt, MAPK and JNK phosphorylations.
BRE exerted differential anti-inflammatory effects between HEMEC and HIMEC following TNF-α/IL-1β activation whereas demonstrated similar anti-angiogenic effects following VEGF stimulation in both cell lines. These findings may provide more insight into the anti-tumorigenic capacities of BRE in human disease and cancer.
doi:10.1016/j.mvr.2014.10.008
PMCID: PMC4275382  PMID: 25446010
3.  A face detection bias for horizontal orientations develops in middle childhood 
Faces are complex stimuli that can be described via intuitive facial features like the eyes, nose, and mouth, “configural” features like the distances between facial landmarks, and features that correspond to computations performed in the early visual system (e.g., oriented edges). With regard to this latter category of descriptors, adult face recognition relies disproportionately on information in specific spatial frequency and orientation bands: many recognition tasks are performed more accurately when adults have access to mid-range spatial frequencies (8–16 cycles/face) and horizontal orientations (Dakin and Watt, 2009). In the current study, we examined how this information bias develops in middle childhood. We recruited children between the ages of 5–10 years-old to participate in a simple categorization task that required them to label images according to whether they depicted a face or a house. Critically, children were presented with face and house images comprised either of primarily horizontal orientation energy, primarily vertical orientation energy, or both horizontal and vertical orientation energy. We predicted that any bias favoring horizontal information over vertical should be more evident in faces than in houses, and also that older children would be more likely to show such a bias than younger children. We designed our categorization task to be sufficiently easy that children would perform at near-ceiling accuracy levels, but with variation in response times that would reflect how they rely on different orientations as a function of age and object category. We found that horizontal bias for face detection (but not house detection) correlated significantly with age, suggesting an emergent category-specific bias for horizontal orientation energy that develops during middle childhood. These results thus suggest that the tuning of high-level recognition to specific low-level visual features takes place over several years of visual development.
doi:10.3389/fpsyg.2015.00772
PMCID: PMC4459095  PMID: 26106349
face detection; spatial vision; visual development
4.  EUK-207 protects human intestinal microvascular endothelial cells (HIMEC) against irradiation-induced apoptosis through the Bcl2 pathway 
Life sciences  2012;91(15-16):771-782.
Aim
To elucidate the signaling mechanisms involved in the protective effect of EUK-207 against irradiation-induced cellular damage and apoptosis in human intestinal microvasculature endothelial cells (HIMEC).
Methods
HIMECs were irradiated and treated with EUK-207. Using hydroethidine and DCF-DA fluorescent probe the intracellular superoxide and reactive oxygen species (ROS) were determined. By real-time PCR and western blotting caspase-3, Bcl2 and Bax genes and proteins were analyzed. Proliferation was determined by [3H]-thymidine uptake. Immunofluorescence staining was used for translocation of p65 NFκB subunit.
Key finding
Irradiation increased ROS production, apoptosis, Bax, Caspase3 and NFkB activity in HIMEC and inhibited cell survival/growth/proliferation. EUK-207 restored the endothelial functions, markedly inhibited the ROS, up-regulated the Bcl2 and down-regulated Bax and prevented NFκB caspase 3 activity in HIMEC.
Significance
HIMEC provide a novel model to define the effect of irradiation induced endothelial dysfunction. Our findings suggest that EUK-207 effectively inhibits the damaging effect of irradiation.
doi:10.1016/j.lfs.2012.08.018
PMCID: PMC3520131  PMID: 22940617
HIMEC; Irradiation; superoxide dismutase; oxyradical; EUK-207; NFκB
5.  Neuronal Plasticity in the Cingulate Cortex of Rats following Esophageal Acid Exposure in Early Life 
Gastroenterology  2011;141(2):544-552.
Background & Aims
The cingulate cortex (CC) has been reported to be involved in processing pain of esophageal origin. However, little is known about molecular changes and cortical activation that arise from early-life, esophageal acid reflux. Excitatory neurotransmission via activation of the N-methyl-D-aspartate (NMDA) receptor and its interaction with post-synaptic density protein-95 (PSD-95) at the synapse appears to mediate neuronal development and plasticity. We investigated the effect of early-life esophageal acid exposure on NMDA receptor subunits and PSD-95 expression in the developing CC.
Methods
We assessed NMDA receptor subunits and PSD-95 protein expression in rostral CC (rCC) tissues of rats exposed to esophageal acid or saline (control), either during post-natal days 7–14 (P7–P14) and/or acutely, at adult stage (P60), using immunoblot and immunoprecipitation analyses.
Results
Compared with controls, acid exposure from P7 to P14 significantly increased expression of NR1, NR2A, and PSD-95, measured 6 weeks after exposure. However, acute exposure at P60 caused a transient increase in expression of NMDA receptor subunits. These molecular changes were more robust in animals exposed to acid neonatally and rechallenged, acutely, at P60. Esophageal acid exposure induced calcium calmodulin kinase II-mediated phosphorylation of the subunit NR2B at Ser1303.
Conclusions
Esophageal acid exposure during early stages of life has long-term effects, because of phosphorylation of the NMDA receptor and overexpression in the rCC. This molecular alteration in the rCC might mediate sensitization of patients with acid-induced esophageal disorders.
doi:10.1053/j.gastro.2011.04.044
PMCID: PMC3152593  PMID: 21616075
brain; developmental neuroscience; pain processing; CamKII
6.  Neonatal Cystitis-Induced Colonic Hypersensitivity in Adult Rats: A Model of Viscero-Visceral Convergence 
Background
The objective of this study was to determine if neonatal cystitis alters colonic sensitivity later in life and to investigate the role of peripheral mechanisms.
Methods
Neonatal rats received intravesical zymosan, normal saline, or anesthesia only for three consecutive days (postnatal days 14th–16th). The estrous cycle phase was determined prior to recording the visceromotor response (VMR) to colorectal distension (CRD) in adult rats. Eosinophils and mast cells were examined from colon and bladder tissue. CRD or urinary bladder distension (UBD)-sensitive pelvic nerve afferents (PNAs) were identified and their responses to distension were examined. The relative expression of N-methyl-D-aspartic acid (NMDA) NR1 subunit in the L6-S1 spinal cord was examined using Western blot.
Results
The VMR to CRD (≥10mmHg) in the neonatal zymosan group was significantly higher than control in both the diestrus, estrus phase and in all phases combined. There was no difference in the total number of eosinophils, mast cells or number of degranulated mast cells between groups. The spontaneous firing of UBD, but not CRD-sensitive PNAs from the zymosan rats was significantly higher than the control. However, the mechanosensitive properties of PNAs to CRD or UBD were no different between groups (p > 0.05). The expression of spinal NR1 subunit was significantly higher in zymosan-treated rats compared to saline treated rats (p <0.05).
Conclusion
Neonatal cystitis results in colonic hypersensitivity in adult rats without changing tissue histology or the mechanosensitive properties of CRD-sensitive PNAs. Neonatal cystitis does results in overexpression of spinal NR1 subunit in adult rats.
doi:10.1111/j.1365-2982.2011.01724.x
PMCID: PMC3117950  PMID: 21592255
cystitis; visceral hyperalgesia; neonatal; viscero-visceral convergence

Results 1-6 (6)