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Garretson X.T.,Georgia State University | Teubner B.J.,Georgia State University | Grove K.L.,Oregon Health And Science University | Vazdarjanova A.,Georgia Regents University | And 3 more authors.
Journal of Neuroscience | Year: 2015

Peroxisome proliferator-activated receptor γ (PPARγ) is clinically targeted for type II diabetes treatment; however, rosiglitazone (ROSI), a PPARγ agonist, increases food intake and body/fat mass as side-effects. Mechanisms for these effects and the role of PPARγ in feeding are not understood. Therefore, we tested this role in Siberian hamsters, a model of human energy balance, and C57BL/6 mice. We tested the following: (1) how ROSI and/or GW9662 (2-chloro-5-nitro-N-phenylbenzamide;PPARγ antagonist) injected intraperitoneally or into the third ventricle (3V) affected Siberian hamster feeding behaviors; (2) whether food deprivation (FD) co-increases agouti-related protein (AgRP) and PPARγ mRNAexpression in Siberian hamsters and mice; (3) whether intraperitoneally administered ROSI increases AgRP andNPYin ad libitum-fed animals; (4) whether intraperitoneally administeredPPARγ antagonism blocks FD-induced increases in AgRP and NPY; and finally, (5) whether intraperitoneally administered PPAR γ modulation affects plasma ghrelin. Third ventricular and intraperitoneally administered ROSI increased food hoarding and intake for 7 d, an effect attenuated by 3V GW9662, and also prevented (intraperitoneal) FD-induced feeding. FD hamsters and mice increased AgRP within the arcuate hypothalamic nucleus with concomitant increases in PPAR γ exclusively within AgRP/NPY neurons. ROSI increased AgRP and NPY similarly to FD, and GW9662 prevented FD-induced increases in AgRP and NPY in both species. Neither ROSI nor GW9662 affected plasma ghrelin. Thus, we demonstrated that PPAR γ activation is sufficient to trigger food hoarding/intake, increase AgRP/NPY, and possibly is necessary for FD-induced increases in feeding and AgRP/NPY. These findings provide initial evidence that FD-induced increases in AgRP/NPY may be a direct PPARγ-dependent process that controls ingestive behaviors. ©2015 the authors.

Ward R.,Augusta University | Ergul A.,Augusta University | Ergul A.,Charlie Norwood Veterans Administration Medical Center
Life Sciences | Year: 2016

Diabetes increases the risk and worsens the progression of cognitive decline. Diabetic rats treated with the dual endothelin receptor antagonist bosentan, have been shown to improve hippocampal-based cognitive deficits. The NLRP3 inflammasome has been implicated in vascular complications of diabetes. We hypothesized that diabetes-mediated increase in endothelin-1 (ET-1) in hippocampal cells causes NLRP3 activation and inflammation. An in vitro model was employed by exposing HT22 hippocampal cells to normal (25. mM), low (5.5. mM) and high (50. mM) glucose conditions with and without palmitate (200. μM) in the presence and absence of 10. μM bosentan for 24. h. NLRP3 activity was measured by western blotting for cryopyrin and caspase-1. ET-1 and IL-1β expression was determined by ELISA. HT22 cells synthesize high levels of ET-1 in normal conditions, which was reduced with palmitate and bosentan as well as low and high glucose conditions. Decreased ET-1 levels were associated with greater activation of NLRP3 and IL-1β in normal glucose. High glucose increased NLRP3 markers and activation compared to normal and low glucose. These data suggest that ET-1 may be protective to neurons. Although endothelin antagonism may be beneficial in improving vascular dysfunction and cognitive impairment, its impact on hippocampal neurons should be further explored. © 2015.

Weinberger P.M.,Georgia Regents University | Merkley M.A.,Georgia Regents University | Khichi S.S.,Georgia Regents University | Lee J.R.,Charlie Norwood Veterans Administration Medical Center | And 3 more authors.
Laryngoscope | Year: 2010

Objectives/Hypothesis: Mortality for black males with head and neck squamous cell carcinoma (HNSCC) is twice that of white males or females. Human papillomavirus (HPV)-active HNSCC, defined by the concurrent presence of high-risk type HPV DNA and host cell p16INK4a expression, is associated with decreased mortality. We hypothesized that prevalence of this HPV-active disease class would be lower in black HNSCC patients compared to white patients. Study Design: Multi-institutional retrospective cohort analysis. Methods: Real-time polymerase chain reaction was used to evaluate for high-risk HPV DNA presence. Immunohistochemistry for p16INK4a protein was used as a surrogate marker for HPV oncoprotein activity. Patients were classified as HPV-negative (HPV DNA-negative, p16INK4a low), HPV-inactive (HPV DNA-positive, p16INK4a low), and HPV-active (HPV DNA-positive, p16INK4a high). Overall survival and recurrence rates were compared by Fisher exact test and Kaplan-Meier analysis. Results: There were 140 patients with HNSCC who met inclusion criteria. Self-reported ethnicity was white (115), black (25), and other (0). Amplifiable DNA was recovered from 102/140 patients. The presence of HPV DNA and the level of p16INK4a expression were determined, and the results were used to classify these patients as HPV-negative (44), HPV-inactive (33), and HPV-active (25). Patients with HPV-active HNSCC had improved overall 5-year survival (59.7%) compared to HPV-negative and HPV-inactive patients (16.9%) (P = .003). Black patients were less likely to have HPV-active disease (0%) compared to white patients (21%) (P = .017). Conclusions: The favorable HPV-active disease class is less common in black than in white patients with HNSCC, which appears to partially explain observed ethnic health disparities. © 2010 The American Laryngological, Rhinological and Otological Society, Inc.

Singh N.,Georgia Regents University | Gurav A.,Georgia Regents University | Sivaprakasam S.,Georgia Regents University | Brady E.,Georgia Regents University | And 9 more authors.
Immunity | Year: 2014

Commensal gut microflora and dietary fiber protect against colonic inflammation and colon cancer through unknown targets. Butyrate, a bacterial product from fermentation of dietary fiber in the colon, has been implicated in this process. GPR109A (encoded by Niacr1) is a receptor for butyrate in the colon. GPR109A is also a receptor for niacin, which is also produced by gut microbiota and suppresses intestinal inflammation. Here we showed that Gpr109a signaling promoted anti-inflammatory properties in colonic macrophages and dendritic cells and enabled them to induce differentiation of Treg cells and IL-10-producing Tcells. Moreover, Gpr109a was essential for butyrate-mediated induction of IL-18 incolonicepithelium. Consequently, Niacr1-/- mice were susceptible to development of colonic inflammation and colon cancer. Niacin, a pharmacological Gpr109a agonist, suppressed colitis and colon cancer in a Gpr109a-dependent manner. Thus, Gpr10a has an essential role in mediating the beneficial effects of gut microbiota and dietary fiber in colon. © 2014 Elsevier Inc.

Buccafusco J.J.,Georgia Regents University | Buccafusco J.J.,Charlie Norwood Veterans Administration Medical Center | Terry Jr. A.V.,Georgia Regents University | Vazdarjanova A.,Charlie Norwood Veterans Administration Medical Center | And 3 more authors.
Pain | Year: 2010

Current clinical treatments for neuropathic pain include amitriptyline, a tricyclic antidepressant with mixed pharmacology that is also clinically reported to impair cognitive performance; and gabapentin, a compound that selectively interacts with α2δ-1 calcium channel subunits. Since few assessments of cognitive performance have been made in non-human primates with these marketed treatments, the purpose of this study was to determine their relative abilities to alter working memory as measured in mature macaques in their performance of a delayed matching-to-sample task. Four delay intervals of increasing duration provided increasing impairment in task accuracies during vehicle sessions. Administration of clinically relevant doses of amitriptyline significantly decreased task accuracy at the highest dose tested (3 mg/kg). Administration of gabapentin increased mean task accuracy, though the effect was not statistically significant until intra-subject variability was reduced by selecting the individual best dose for each animal (which averaged 12.8 mg/kg). Most of the effect was obtained during the presentation of long delay trials (18.2% above vehicle). Task improvement was sustained during sessions run 24 h after gabapentin administration. In a series that used a task-relevant distractor to determine gabapentin's effect on attention, drug treatment reversed distractor-impaired accuracy during long delay trials (25.4% above vehicle). The selective improvement in long delay accuracy in both paradigms suggests improvement in encoding or retention components of working memory. It is currently unclear whether the ability of acute administration of gabapentin to modestly improve working memory occurs by a mechanism that could be related to its anti-allodynic mechanism of action.

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