Browsing by Subject "COX-2"

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    Alcohol reinstatement after prolonged abstinence from alcohol drinking by female adolescent rats: Roles of cyclooxygenase-2 and the prostaglandin E2 receptor 1
    (Elsevier, 2022) Kline, Hannah L.; Yamamoto, Bryan K.; Pharmacology and Toxicology, School of Medicine
    Background: Adolescent alcohol misuse is a global problem that can significantly increase the reinstatement of alcohol drinking during re-exposure after abstinence, but the mechanism that causes this increase is unknown. Female adolescents are an understudied population but they are particularly vulnerable to adolescent-onset alcohol abuse. We aimed to determine how adolescent-onset alcohol drinking affects pro-inflammatory mediators endothelin-1 (ET-1), cyclooxygenase-2 (COX-2), and prostaglandin E2 (PGE2) in the brain and the role of COX-2 and PGE2 in EtOH reinstatement in adolescent females. Methods: Adolescent female rats were exposed to a 2-bottle choice paradigm of water vs 5% ethanol (EtOH) every other day over a 21 day period. ET-1 and COX-2 proteins were measured in the dorsal striatum (DS) after a 4 week abstinence from EtOH drinking. The COX-2 inhibitor nimesulide was then administered during abstinence prior to an EtOH reinstatement or sucrose preference or to measure PGE2 content. The PGE2 receptor 1 (EP1) antagonist SC-51089 was then administered prior to EtOH reinstatement during which EtOH intake was measured. Results: EtOH drinking significantly increased ET-1 by 33.8 ± 8.9% and COX-2 by 71.4 ± 24.3% in the DS. Treatment with nimesulide during abstinence attenuated EtOH intake during reinstatement after prolonged abstinence by 40.3 ± 12.4% compared to saline controls. Adolescent EtOH drinking and abstinence increased PGE2 150.5 ± 30.9% in the DS and nimesulide attenuated this increase. SC-51089 treatment during abstinence attenuated EtOH reinstatement by 48.1 ± 8.4% compared to DMSO controls. Conclusions: These experiments identified a prostaglandin-mediated mechanism that offers a putative pharmacological target to attenuate EtOH reinstatement after adolescent-onset EtOH drinking.
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    Cyclooxygenase-2 Expression in Hamster and Human Pancreatic Neoplasia
    (Elsevier, 2006-06) Crowell, Pamela L.; Schmidt, C. Max; Yip-Schneider, Michele T.; Savage, Jesse J.; Hertzler II, Dean A.; Cummings, William O.; Biochemistry and Molecular Biology, School of Medicine
    Cyclooxygenase-2 (COX-2) has been implicated in the development of gastrointestinal malignancies. The aim of the present study was to determine COX-2 expression/activity throughout stages of experimental and human pancreatic neoplasia. COX-2 immunohistochemistry was performed in pancreata of hamsters subjected to the carcinogen N-nitrosobis-(2-oxopropyl)amine (BOP) and in human pancreatic tumors. COX-2 activity was determined by prostaglandin E2 assay in tumor versus matched normal pancreatic tissues. The activity of the COX inhibitor sulindac was tested in the PC-1 hamster pancreatic cancer model. COX-2 expression was elevated in all pancreatic intraepithelial neoplasias (PanINs) and adenocarcinomas. In BOP-treated hamsters, there were significant progressive elevations in COX-2 expression throughout pancreatic tumorigenesis. In human samples, peak COX-2 expression occurred in PanIN2 lesions and remained moderately elevated in PanIN3 and adenocarcinoma tissues. COX-2 activity was significantly elevated in hamster and human pancreatic cancers compared to pair-matched normal pancreas. Furthermore, hamster pancreatic tumor engraftment/formation in the PC-1 hamster pancreatic cancer model was reduced 4.9-fold by oral administration of sulindac. Increased COX-2 expression is an early event in pancreatic carcinogeneses. The BOP-induced hamster carcinogenesis model is a representative model used to study the role of COX-2 in well-differentiated pancreatic tumorigenesis. COX inhibitors may have a role in preventing tumor engraftment/formation.
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    The peroxisome proliferator-activated receptor γ antagonist, GW9962, alters UVB-induced inflammatory responses, apoptosis, and delayed hyperproliferation
    (2009-01-16T17:25:58Z) Martel, Kellie Clay; Konger, Raymond L.; Travers, Jeffrey B.; Spandau, Dan F, 1957-
    It has recently been shown that the gamma subtype of the peroxisome proliferator-activated receptor (PPARγ) is a target of ultraviolet B (290-320 nm; UVB) irradiation, and that PPARγ activation is necessary for full UVB-induced cyclooxygenase-2 (COX-2) induction. However, the biological significance of PPARγ activation in cutaneous photobiology is unknown. Acute UVB irradiation results in a characteristic series of events in the epidermis which includes: an initial edema response and subsequent inflammation, COX-2 induction, apoptosis, and a delayed hyperproliferative response. Therefore, the regulatory role of PPARγ activation was examined in this acute photoresponse using a topical application of the potent, irreversible PPARγ antagonist, GW9962. GW9662 was applied to the epidermis of SKH1 hairless albino mice at increasing doses (0.01-1.0mM) prior to UVB irradiation. The photobiological responses were examined through RT-PCR, skin thickness measurements, and immunohistochemistry, at 24 and 72 hours after UVB-irradiation. At the highest dose, GW9622 significantly inhibited UVB-induced inflammation, as measured by COX-2 induction at both 24 and 72 hrs. Inflammation assessed by skin thickness measurements indicated that lower doses mildly increased inflammation at 72 hrs, but suppressed inflammation at the highest dose. In contrast, GW9662 treatment dose dependently augmented UVB-induced apoptosis at 24 hours, while affecting the delayed hyperproliferative response at 72 hours in an inverse dose-response manner. The results from this study suggest that PPARγ is a key regulator of these photobiological responses. Because these responses are well known to be involved in tumor development and progression, this study also suggests a potential role for PPARγ in UVB-induced skin cancers.