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Recent Research Articles from UNTHSC

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Neuronal ablation of p-Akt at Ser473 leads to altered 5-HT1A/2A receptor function.

Wed, 02/04/2015 - 4:35am
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Neuronal ablation of p-Akt at Ser473 leads to altered 5-HT1A/2A receptor function.

Neurochem Int. 2014 Jul;73:113-21

Authors: Saunders C, Siuta M, Robertson SD, Davis AR, Sauer J, Matthies HJ, Gresch PJ, Airey DC, Lindsley CW, Schetz JA, Niswender KD, Veenstra-Vanderweele JM, Galli A

Abstract
The serotonergic system regulates a wide range of behavior, including mood and impulsivity, and its dysregulation has been associated with mood disorders, autism spectrum disorder, and addiction. Diabetes is a risk factor for these conditions. Insulin resistance in the brain is specifically associated with susceptibility to psychostimulant abuse. Here, we examined whether phosphorylation of Akt, a key regulator of the insulin signaling pathway, controls serotonin (5-HT) signaling. To explore how impairment in Akt function regulates 5-HT homeostasis, we used a brain-specific rictor knockout (KO) mouse model of impaired neuronal phosphorylation of Akt at Ser473. Cortical 5-HT1A and 5-HT2A receptor binding was significantly elevated in rictor KO mice. Concomitant with this elevated receptor expression, the 5-HT1A receptor agonist 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) led to an increased hypothermic response in rictor KO mice. The increased cortical 5-HT1A receptor density was associated with higher 5-HT1A receptor levels on the cortical cell surface. In contrast, rictor KO mice displayed significantly reduced head-twitch response (HTR) to the 5-HT2A/C agonist 2,5-dimethoxy-4-iodoamphetamine (DOI), with evidence of impaired 5-HT2A/C receptor signaling. In vitro, pharmacological inhibition of Akt significantly increased 5-HT1A receptor expression and attenuated DOI-induced 5-HT2A receptor signaling, thereby lending credence to the observed in vivo cross-talk between neuronal Akt signaling and 5-HT receptor regulation. These data reveal that defective central Akt function alters 5-HT signaling as well as 5-HT-associated behaviors, demonstrating a novel role for Akt in maintaining neuronal 5-HT receptor function.

PMID: 24090638 [PubMed - indexed for MEDLINE]

Urine osmolality in the US population: implications for environmental biomonitoring.

Wed, 02/04/2015 - 4:35am
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Urine osmolality in the US population: implications for environmental biomonitoring.

Environ Res. 2015 Jan;136:482-90

Authors: Yeh HC, Lin YS, Kuo CC, Weidemann D, Weaver V, Fadrowski J, Neu A, Navas-Acien A

Abstract
BACKGROUND: For many environmental chemicals, concentrations in spot urine samples are considered valid surrogates of exposure and internal dose. To correct for urine dilution, spot urine concentrations are commonly adjusted for urinary creatinine. There are, however, several concerns about the use of urine creatinine. While urine osmolality is an attractive alternative; its characteristics and determinants in the general population remain unknown. Our objective was to describe the determinants of urine osmolality and to contrast the difference between osmolality and creatinine in urine.
METHODS: From the National Health and Nutrition Examination Survey (NHANES) (2009-2010), 10,769 participants aged 16 years or older with measured urine osmolality and creatinine were used in the analysis. Very dilute and very concentrated urine was defined as urine creatinine lower than 0.3g/l and higher than 3g/l, respectively. Linear and logistic regression analyses were performed to investigate the associations of interest.
RESULTS: Urine osmolality and creatinine were highly correlated (Pearson correlation coefficient=0.75) and their respective median values were 648 mOsm/kg and 1.07 g/l. The prevalence of very dilute and very concentrated urine samples was 8.1% and 3.1%, respectively. Factors associated in the same direction with both urine osmolality and urine creatinine included age, sex, race, body mass index (BMI), hypertension, water intake, and blood osmolality. The magnitude of associations expressed as percent change was significantly stronger with creatinine than osmolality. Compared to urine creatinine, urine osmolality did not vary by diabetes status but was affected by daily total protein intake. Participants with chronic kidney disease (CKD) had significantly higher urine creatinine concentrations but lower urine osmolality. Both very dilute and concentrated urine were associated with a diverse array of sociodemographic, medical conditions, and dietary factors. For instance, females were approximately 3.3 times more likely to have urine over-dilution than male [the adjusted odds ratios (95% CI)=3.27 (2.10-5.10)].
CONCLUSION: Although the determinants of urine osmolality were generally similar to those of urine creatinine, the relative influence of socio-demographic and medical conditions was less on urine osmolality than on urine creatinine. Protocols for spot urine sample collection could recommend avoiding excessive and insufficient water intake before urine sampling to improve urine adequacy. The feasibility of adopting urine osmolality adjustment and water intake recommendations before providing spot urine samples for environmental biomonitoring merits further investigation.

PMID: 25460670 [PubMed - indexed for MEDLINE]

Antioxidant activity, antitumor effect, and antiaging property of proanthocyanidins extracted from kunlun chrysanthemum flowers.

Tue, 02/03/2015 - 4:29am
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Antioxidant activity, antitumor effect, and antiaging property of proanthocyanidins extracted from kunlun chrysanthemum flowers.

Oxid Med Cell Longev. 2015;2015:983484

Authors: Jing S, Zhang X, Yan LJ

Abstract
The objective of the present study was to evaluate the antioxidant activity, antitumor effect, and antiaging property of proanthocyanidins from Kunlun Chrysanthemum flowers (PKCF) grown in Xinjiang. In vitro antioxidant experiments results showed that the total antioxidant activity and the scavenging capacity of hydroxyl radicals ((•)OH) and 1,1-diphenyl-2-picrylhydrazyl (DPPH(•)) radicals increased in a concentration-dependent manner and were stronger than those of vitamin C. To investigate the antioxidant activity of PKCF in vivo, we used serum, liver, and kidney from mouse for the measurement of superoxide dismutase (SOD), malondialdehyde (MDA), and total antioxidant capacity (T-AOC). Results indicated that PKCF had antioxidative effect in vivo which significantly improved the activity of SOD and T-AOC and decreased MDA content. To investigate the antitumor activity of PKCF, we used H22 cells, HeLa cells, and Eca-109 cells with Vero cells as control. Inhibition ratio and IC50 values were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay; PKCF showed great inhibitory activity on H22 cells and HeLa cells. We also used fruit flies as a model for analyzing the anti-aging property of PKCF. Results showed that PKCF has antiaging effect on Drosophila. Results of the present study demonstrated that PKCF could be a promising agent that may find applications in health care, medicine, and cosmetics.

PMID: 25628774 [PubMed - in process]

Pharmacological modulation of abnormal involuntary DOI-induced head twitch response in male DBA/2J mice: I. Effects of D2/D3 and D2 dopamine receptor selective compounds.

Tue, 02/03/2015 - 4:29am
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Pharmacological modulation of abnormal involuntary DOI-induced head twitch response in male DBA/2J mice: I. Effects of D2/D3 and D2 dopamine receptor selective compounds.

Neuropharmacology. 2014 Aug;83:18-27

Authors: Rangel-Barajas C, Malik M, Vangveravong S, Mach RH, Luedtke RR

Abstract
Because of the complexity and heterogeneity of human neuropsychiatric disorders, it has been difficult to identify animal models that mimic the symptoms of these neuropathologies and can be used to screen for antipsychotic agents. For this study we selected the murine 5HT2A/2C receptor agonist-induced head twitch response (HTR) induced by the administration of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), which has been proposed as an animal model of symptoms associated with a variety of behavioral and psychiatric conditions. We investigated the DOI-induced HTR in male DBA/2J mice using a panel of D2-like (D2, D3 and D4) and D2 dopamine receptor selective compounds. When DBA/2J mice were administered a daily dose of DOI (5 mg/kg), tolerance to the DOI occurs. However, administrations of the same dose of DOI every other day (48 h) or on a weekly basis did not lead to tolerance and the ability to induce tolerance after daily administration of DOI remains intact after repeated weekly administration of DOI. Subsequently, a panel of D2-like dopamine receptor antagonists was found to effectively inhibit the DOI-induced HTR in DBA/2J mice. However, the benzamide eticlopride, which is a high affinity D2-like antagonist, was a notable exception. SV 293, SV-III-130s and N-methylbenperidol, which exhibit a high affinity for D2 versus the D3 dopamine receptor subtypes (60- to 100-fold binding selectivity), were also found to inhibit the HTR in DBA/2J mice. This observation suggests a functional interaction between dopaminergic and serotonergic systems through D2 dopamine receptors and the 5-HT2A serotonin receptors in vivo.

PMID: 24680675 [PubMed - indexed for MEDLINE]

The therapeutic promise of positive allosteric modulation of nicotinic receptors.

Tue, 02/03/2015 - 4:29am
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The therapeutic promise of positive allosteric modulation of nicotinic receptors.

Eur J Pharmacol. 2014 Mar 15;727:181-5

Authors: Uteshev VV

Abstract
In the central nervous system, deficits in cholinergic neurotransmission correlate with decreased attention and cognitive impairment, while stimulation of neuronal nicotinic acetylcholine receptors improves attention, cognitive performance and neuronal resistance to injury as well as produces robust analgesic and anti-inflammatory effects. The rational basis for the therapeutic use of orthosteric agonists and positive allosteric modulators (PAMs) of nicotinic receptors arises from the finding that functional nicotinic receptors are ubiquitously expressed in neuronal and non-neuronal tissues including brain regions highly vulnerable to traumatic and ischemic types of injury (e.g., cortex and hippocampus). Moreover, functional nicotinic receptors do not vanish in age-, disease- and trauma-related neuropathologies, but their expression and/or activation levels decline in a subunit- and brain region-specific manner. Therefore, augmenting the endogenous cholinergic tone by nicotinic agents is possible and may offset neurological impairments associated with cholinergic hypofunction. Importantly, because neuronal damage elevates extracellular levels of choline (a selective agonist of α7 nicotinic acetylcholine receptors) near the site of injury, α7-PAM-based treatments may augment pathology-activated α7-dependent auto-therapies where and when they are most needed (i.e., in the penumbra, post-injury). Thus, nicotinic-PAM-based treatments are expected to augment the endogenous cholinergic tone in a spatially and temporally restricted manner creating the potential for differential efficacy and improved safety as compared to exogenous orthosteric nicotinic agonists that activate nicotinic receptors indiscriminately. In this review, I will summarize the existing trends in therapeutic applications of nicotinic PAMs.

PMID: 24530419 [PubMed - indexed for MEDLINE]

Sigma-1 receptor stimulation protects retinal ganglion cells from ischemia-like insult through the activation of extracellular-signal-regulated kinases 1/2.

Tue, 02/03/2015 - 4:29am
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Sigma-1 receptor stimulation protects retinal ganglion cells from ischemia-like insult through the activation of extracellular-signal-regulated kinases 1/2.

Exp Eye Res. 2014 Nov;128:156-69

Authors: Mueller BH, Park Y, Ma HY, Dibas A, Ellis DZ, Clark AF, Yorio T

Abstract
Sigma-1 receptor (σ-1) activation and mitogen-activated protein kinases (MAPKs) have been shown to protect retinal ganglion cells (RGCs) from cell death. The purpose of this study was to determine if σ-1 receptor stimulation with pentazocine could promote neuroprotection under conditions of an ischemia-like insult (oxygen glucose deprivation (OGD)) through the phosphorylation of extracellular signal regulated kinase (pERK)1/2. Primary RGCs were isolated from P3-P7 Sprague-Dawley rats and purified by sequential immunopanning using Thy1.1 antibodies. RGCs were cultured for 7 days before subjecting the cells to an OGD insult (0.5% oxygen in glucose-free medium) for 6 h. During the OGD, RGCs were treated with pentazocine (σ-1 receptor agonist) with or without BD 1047 (σ-1 receptor antagonist). In other experiments, primary RGCs were treated with pentazocine in the presence or absence of an MEK1/2 inhibitor, PD098059. Cell survival/death was assessed by staining with the calcein-AM/ethidium homodimer reagent. Levels of pERK1/2, total ERK1/2, and beta tubulin expression were determined by immunoblotting and immunofluorescence staining. RGCs subjected to OGD for 6 h induced 50% cell death in primary RGCs (p < 0.001) and inhibited pERK1/2 expression by 65% (p < 0.001). Cell death was attenuated when RGCs were treated with pentazocine under OGD (p < 0.001) and pERK1/2 expression was increased by 1.6 fold (p < 0.05) compared to OGD treated RGCs without pentazocine treatment. The co-treatment of PD098059 (MEK1/2 inhibitor) with pentazocine significantly abolished the protective effects of pentazocine on the RGCs during this OGD insult. Activation of the σ-1 receptor is a neuroprotective target that can protect RGCs from an ischemia-like insult. These results also established a direct relationship between σ-1 receptor stimulation and the neuroprotective effects of the ERK1/2 pathway in purified RGCs subjected to OGD. These findings suggest that activation of the σ-1 receptor may be a therapeutic target for neuroprotection particularly relevant to ocular neurodegenerative diseases that effect RGCs.

PMID: 25305575 [PubMed - indexed for MEDLINE]

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