Recent Research Articles from UNTHSC

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Exosome-associated hepatitis C virus in cell cultures and patient plasma.

Fri, 02/13/2015 - 4:30am
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Exosome-associated hepatitis C virus in cell cultures and patient plasma.

Biochem Biophys Res Commun. 2014 Dec 12;455(3-4):218-22

Authors: Liu Z, Zhang X, Yu Q, He JJ

Abstract
Hepatitis C virus (HCV) infects its target cells in the form of cell-free viruses and through cell-cell contact. Here we report that HCV is associated with exosomes. Using highly purified exosomes and transmission electron microscopic imaging, we demonstrated that HCV occurred in both exosome-free and exosome-associated forms. Exosome-associated HCV was infectious and resistant to neutralization by an anti-HCV neutralizing antibody. There were more exosome-associated HCV than exosome-free HCV detected in the plasma of HCV-infected patients. These results suggest exosome-associated HCV as an alternative form for HCV infection and transmission.

PMID: 25449270 [PubMed - indexed for MEDLINE]

The Critical Need to Promote Research of Aging and Aging-related Diseases to Improve Health and Longevity of the Elderly Population.

Wed, 02/11/2015 - 4:31am
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The Critical Need to Promote Research of Aging and Aging-related Diseases to Improve Health and Longevity of the Elderly Population.

Aging Dis. 2015 Feb;6(1):1-5

Authors: Jin K, Simpkins JW, Ji X, Leis M, Stambler I

Abstract
Due to the aging of the global population and the derivative increase in aging-related non-communicable diseases and their economic burden, there is an urgent need to promote research on aging and aging-related diseases as a way to improve healthy and productive longevity for the elderly population. To accomplish this goal, we advocate the following policies: 1) Increasing funding for research and development specifically directed to ameliorate degenerative aging processes and to extend healthy and productive lifespan for the population; 2) Providing a set of incentives for commercial, academic, public and governmental organizations to foster engagement in such research and development; and 3) Establishing and expanding coordination and consultation structures, programs and institutions involved in aging-related research, development and education in academia, industry, public policy agencies and at governmental and supra-governmental levels.

PMID: 25657847 [PubMed]

HIV-1 Tat Alters Neuronal Autophagy by Modulating Autophagosome Fusion to the Lysosome: Implications for HIV-Associated Neurocognitive Disorders.

Sat, 02/07/2015 - 4:33am

HIV-1 Tat Alters Neuronal Autophagy by Modulating Autophagosome Fusion to the Lysosome: Implications for HIV-Associated Neurocognitive Disorders.

J Neurosci. 2015 Feb 4;35(5):1921-38

Authors: Fields J, Dumaop W, Elueteri S, Campos S, Serger E, Trejo M, Kosberg K, Adame A, Spencer B, Rockenstein E, He JJ, Masliah E

Abstract
Antiretroviral therapy has increased the life span of HIV+ individuals; however, HIV-associated neurocognitive disorder (HAND) occurrence is increasing in aging HIV patients. Previous studies suggest HIV infection alters autophagy function in the aging CNS and HIV-1 proteins affect autophagy in monocyte-derived cells. Despite these findings, the mechanisms leading to dysregulated autophagy in the CNS remain unclear. Here we sought to determine how HIV Tat dysregulates autophagy in neurons. Tat caused a dose-dependent decrease in autophagosome markers, microtubule-associated protein-1 light chain β II (LC3II), and sequestosome 1(SQSTM1), in a membrane-enriched fraction, suggesting Tat increases autophagic degradation. Bafilomycin A1 increased autophagosome number, LC3II, and SQSTM1 accumulation; Tat cotreatment diminished this effect. Tat had no effect when 3-methyladenine or knockdown of beclin 1 blocked early stages of autophagy. Tat increased numbers of LC3 puncta and resulted in the formation of abnormal autophagosomes in vitro. Likewise, in vivo studies in GFAP-Tat tg mice showed increased autophagosome accumulation in neurons, altered LC3II levels, and neurodegeneration. These effects were reversed by rapamycin treatment. Tat colocalized with autophagosome and lysosomal markers and enhanced the colocalization of autophagosome with lysosome markers. Furthermore, co-IP studies showed that Tat interacts with lysosomal-associated membrane protein 2A (LAMP2A) in vitro and in vivo, and LAMP2A overexpression reduces Tat-induced neurotoxicity. Hence, Tat protein may induce autophagosome and lysosome fusion through interaction with LAMP2A leading to abnormal neuronal autophagy function and dysregulated degradation of critical intracellular components. Therapies targeting Tat-mediated autophagy alterations may decrease neurodegeneration in aging patients with HAND.

PMID: 25653352 [PubMed - in process]

Autonomic neural control of heart rate during dynamic exercise: revisited.

Fri, 02/06/2015 - 4:30am
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Autonomic neural control of heart rate during dynamic exercise: revisited.

J Physiol. 2014 Jun 15;592(Pt 12):2491-500

Authors: White DW, Raven PB

Abstract
UNLABELLED: The accepted model of autonomic control of heart rate (HR) during dynamic exercise indicates that the initial increase is entirely attributable to the withdrawal of parasympathetic nervous system (PSNS) activity and that subsequent increases in HR are entirely attributable to increases in cardiac sympathetic activity. In the present review, we sought to re-evaluate the model of autonomic neural control of HR in humans during progressive increases in dynamic exercise workload. We analysed data from both new and previously published studies involving baroreflex stimulation and pharmacological blockade of the autonomic nervous system. Results indicate that the PSNS remains functionally active throughout exercise and that increases in HR from rest to maximal exercise result from an increasing workload-related transition from a 4 : 1 vagal-sympathetic balance to a 4 : 1 sympatho-vagal balance. Furthermore, the beat-to-beat autonomic reflex control of HR was found to be dependent on the ability of the PSNS to modulate the HR as it was progressively restrained by increasing workload-related sympathetic nerve activity.
IN CONCLUSION: (i) increases in exercise workload-related HR are not caused by a total withdrawal of the PSNS followed by an increase in sympathetic tone; (ii) reciprocal antagonism is key to the transition from vagal to sympathetic dominance, and (iii) resetting of the arterial baroreflex causes immediate exercise-onset reflexive increases in HR, which are parasympathetically mediated, followed by slower increases in sympathetic tone as workloads are increased.

PMID: 24756637 [PubMed - indexed for MEDLINE]

High therapeutic potential of positive allosteric modulation of α7 nAChRs in a rat model of traumatic brain injury: Proof-of-concept.

Thu, 02/05/2015 - 4:32am

High therapeutic potential of positive allosteric modulation of α7 nAChRs in a rat model of traumatic brain injury: Proof-of-concept.

Brain Res Bull. 2015 Jan 31;

Authors: Gatson JW, Simpkins JW, Uteshev VV

Abstract
There are currently no clinically-efficacious drug therapies to treat brain damage secondary to traumatic brain injury (TBI). In this proof-of-concept study, we used a controlled cortical impact model of TBI in young adult rats to explore a novel promising approach that utilizes PNU-120596, a previously-reported highly selective Type-II positive allosteric modulator (α7-PAM) of α7 nicotinic acetylcholine receptors (nAChRs). α7-PAMs enhance and prolong α7 nAChR activation, but do not activate α7 nAChRs when administered without an agonist. The rational basis for the use of an α7-PAM as a post-TBI treatment is tripartite and arises from: 1) the intrinsic ability of brain injury to elevate extracellular levels of choline (a ubiquitous cell membrane-building material and a selective endogenous agonist of α7 nAChRs) due to the breakdown of cell membranes near the site and time of injury; 2) the ubiquitous expression of functional α7 nAChRs in neuronal and glial/immune brain cells; and 3) the potent neuroprotective and anti-inflammatory effects of α7 nAChR activation. Therefore, both neuroprotective and anti-inflammatory effects can be achieved post-TBI by targeting only a single player (i.e., the α7 nAChR) using α7-PAMs to enhance the activation of α7 nAChRs by injury-elevated extracellular choline. Our data support this hypothesis and demonstrate that subcutaneous administration of PNU-120596 post-TBI in young adult rats significantly reduces both brain cell damage and reactive gliosis. Therefore, our results introduce post-TBI systemic administration of α7-PAMs as a promising therapeutic intervention that could significantly restrict brain injury post-TBI and facilitate recovery of TBI patients.

PMID: 25647232 [PubMed - as supplied by publisher]

Population genetics of 23 Y-STR markers in Kuwaiti population.

Thu, 02/05/2015 - 4:32am

Population genetics of 23 Y-STR markers in Kuwaiti population.

Forensic Sci Int Genet. 2015 Jan 17;16C:203-204

Authors: Taqi Z, Alenizi M, Alenizi H, Ismael S, Dukhyil AA, Nazir M, Sanqoor S, Al Harbi E, Al-Jaber J, Theyab J, Moura-Neto RS, Budowle B

PMID: 25643873 [PubMed - as supplied by publisher]

AMPA Receptor Desensitization is the Determinant of AMPA Receptor Mediated Excitotoxicity in Purified Retinal Ganglion Cells.

Thu, 02/05/2015 - 4:32am

AMPA Receptor Desensitization is the Determinant of AMPA Receptor Mediated Excitotoxicity in Purified Retinal Ganglion Cells.

Exp Eye Res. 2015 Jan 30;

Authors: Park YH, Mueller BH, McGrady NR, Ma HY, Yorio T

Abstract
The ionotropic glutamate receptors (iGLuR) have been hypothesized to play a role in neuronal pathogenesis by mediating excitotoxic death. Previous studies on iGluR in the retina have focused on two broad classes of receptors: NMDA and non-NMDA receptors including the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor (AMPAR) and kainate receptor. In this study, we examined the role of receptor desensitization on the specific excitotoxic effects of AMPAR activation on primary retinal ganglion cells (RGCs). Purified rat RGCs were isolated from postnatal day 4-7 Sprague-Dawley rats. Calcium imaging was used to identify the functionality of the AMPARs and selectivity of the s-AMPA agonist. Phosphorylated CREB and ERK1/2 expression were performed following s-AMPA treatment. s-AMPA excitotoxicity was determined by JC-1 mitochondrial membrane depolarization assay, caspase3/7 luciferase activity assay, immunoblot analysis for α-fodrin, and Live (calcein AM)/Dead (ethidium homodimer-1) assay. RGC cultures of 98% purity, lacking Iba1 and GFAP expression were used for the present studies. Isolated prenatal RGCs expressed calcium permeable AMPAR and s-AMPA (100μM) treatment of cultured RGCs significantly increased phosphorylation of CREB but not that of ERK1/2. A prolonged (6 hours) AMPAR activation in purified RGCs using s-AMPA (100μM) did not depolarize the RGC mitochondrial membrane potential. In addition, treatment of cultured RGCs with s-AMPA, both in the presence and absence of trophic factors (BDNF and CNTF), did not increase caspase 3/7 activities or the cleavage of α-fodrin (neuronal apoptosis marker), as compared to untreated controls. Lastly, a significant increase in cell survival of RGCs was observed after s-AMPA treatment as compared to control untreated RGCs. However, preventing the desensitization of AMPAR with the treatment with either kainic acid (100μM) or the combination of s-AMPA and cyclothiazide (50μM) significantly reduced cell survivability. Activation of the AMPAR in RGCs does not appear to activate a signaling cascade to apoptosis, suggesting that RGCs in vitro are not susceptible to AMPA excitotoxicity as previously hypothesized. Conversely, preventing AMPAR desensitization through differential agonist activation caused AMPAR mediated excitotoxicity. Activation of the AMPAR in increasing CREB phosphorylation was dependent on the presence of calcium, which may help explain this action in increasing RGC survival.

PMID: 25643624 [PubMed - as supplied by publisher]

Indoor air pollution from solid fuels and peripheral blood DNA methylation: findings from a population study in Warsaw, Poland.

Thu, 02/05/2015 - 4:32am
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Indoor air pollution from solid fuels and peripheral blood DNA methylation: findings from a population study in Warsaw, Poland.

Environ Res. 2014 Oct;134:325-30

Authors: Tao MH, Zhou J, Rialdi AP, Martinez R, Dabek J, Scelo G, Lissowska J, Chen J, Boffetta P

Abstract
DNA methylation is a potential mechanism linking indoor air pollution to adverse health effects. Fetal and early-life environmental exposures have been associated with altered DNA methylation and play a critical role in progress of diseases in adulthood. We investigated whether exposure to indoor air pollution from solid fuels at different lifetime periods was associated with global DNA methylation and methylation at the IFG2/H19 imprinting control region (ICR) in a population-based sample of non-smoking women from Warsaw, Poland. Global methylation and IFG2/H19 ICR methylation were assessed in peripheral blood DNA from 42 non-smoking women with Luminometric Methylation Assay (LUMA) and quantitative pyrosequencing, respectively. Linear regression models were applied to estimate associations between indoor air pollution and DNA methylation in the blood. Compared to women without exposure, the levels of LUMA methylation for women who had ever exposed to both coal and wood were reduced 6.70% (95% CI: -13.36, -0.04). Using both coal and wood before age 20 was associated with 6.95% decreased LUMA methylation (95% CI: -13.79, -0.11). Further, the negative correlations were more significant with exposure to solid fuels for cooking before age 20. There were no clear associations between indoor solid fuels exposure before age 20 and through the lifetime and IFG2/H19 ICR methylation. Our study of non-smoking women supports the hypothesis that exposure to indoor air pollution from solid fuels, even early-life exposure, has the capacity to modify DNA methylation that can be detected in peripheral blood.

PMID: 25199973 [PubMed - indexed for MEDLINE]

Low serum zinc is associated with elevated risk of cadmium nephrotoxicity.

Thu, 02/05/2015 - 4:32am
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Low serum zinc is associated with elevated risk of cadmium nephrotoxicity.

Environ Res. 2014 Oct;134:33-8

Authors: Lin YS, Ho WC, Caffrey JL, Sonawane B

Abstract
BACKGROUND: Despite animal evidence suggests that zinc modulates cadmium nephrotoxicity, limited human data are available.
OBJECTIVE: To test the hypothesis that low serum zinc concentrations may increase the risk of cadmium-mediated renal dysfunction in humans.
METHODS: Data from 1545 subjects aged 20 or older in the National Health and Nutrition Examination Survey (NHANES), 2011-2012 were analyzed. Renal function was defined as impaired when estimated glomerular filtration rate (eGFR) fell below 60 ml/min/1.73 m(2) and/or the urinary albumin-to-creatinine ratio surpassed 2.5 in men and 3.5mg/mmol in women.
RESULTS: Within the study cohort, 117 subjects had reduced eGFR and 214 had elevated urinary albumin. After adjusting for potential confounders, subjects with elevated blood cadmium (>0.53 μg/L) were more likely to have a reduced eGFR (odds ratio [OR]=2.21, 95% confidence interval [CI]: 1.09-4.50) and a higher urinary albumin (OR=2.04, 95% CI: 1.13-3.69) than their low cadmium (<0.18 μg/L) peers. In addition, for any given cadmium exposure, low serum zinc is associated with elevated risk of reduced eGFR (OR=3.38, 95% CI: 1.39-8.28). A similar increase in the odds ratio was observed between declining serum zinc and albuminuria but failed to reach statistical significance. Those with lower serum zinc/blood cadmium ratios were likewise at a greater risk of renal dysfunction (p<0.01).
CONCLUSIONS: This study results suggest that low serum zinc concentrations are associated with an increased risk of cadmium nephrotoxicity. Elevated cadmium exposure is global public health issue and the assessment of zinc nutritional status may be an important covariate in determining its effective renal toxicity.

PMID: 25042034 [PubMed - indexed for MEDLINE]

Development of reusable logic for determination of statin exposure-time from electronic health records.

Wed, 02/04/2015 - 4:35am
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Development of reusable logic for determination of statin exposure-time from electronic health records.

J Biomed Inform. 2014 Jun;49:206-12

Authors: Miller AW, McCarty CA, Broeckel U, Hytopoulos V, Cross DS

Abstract
OBJECTIVE: We aim to quantify HMG-CoA reductase inhibitor (statin) prescriber-intended exposure-time using a generalizable algorithm that interrogates data stored in the electronic health record (EHR).
MATERIALS AND METHODS: This study was conducted using the Marshfield Clinic (MC) Personalized Medicine Research Project (PMRP) a central Wisconsin-based population and biobank with, on average, 30 years of electronic health data available in the independently-developed MC Cattails MD EHR. Individuals with evidence of statin exposure were identified from the electronic records, and manual chart abstraction of all mentions of prescribed statins was completed. We then performed electronic chart abstraction of prescriber-intended exposure time for statins, using previously identified logic to capture pill-splitting events, normalizing dosages to atorvastatin-equivalent dose. Four models using iterative training sets were tested to capture statin end-dates. Calculated cumulative provider-intended exposures were compared to manually abstracted gold-standard measures of ordered statin prescriptions, and aggregate model results (totals) for training and validation populations were compared. The most successful model was the one with the smallest discordance between modeled and manually abstracted Atorvastatin 10mg/year Equivalents (AEs).
RESULTS: Of the approximately 20,000 patients enrolled in the PMRP, 6243 were identified with statin exposure during the study period (1997-2011), 59.8% of whom had been prescribed multiple statins over an average of approximately 11 years. When the best-fit algorithm was implemented and validated by manual chart review for the statin-ordered population, it was found to capture 95.9% of the correlation between calculated and expected statin provider-intended exposure time for a random validation set, and the best-fit model was able to predict intended statin exposure to within a standard deviation of 2.6 AEs, with a standard error of +0.23 AEs.
CONCLUSION: We demonstrate that normalized provider-intended statin exposure time can be estimated using a combination of structured clinical data sources, including a medications ordering system and a clinical appointment coordination system, supplemented with text data from clinical notes.

PMID: 24637142 [PubMed - indexed for MEDLINE]

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]

Autosomal and Y-STR analysis of degraded DNA from the 120-year-old skeletal remains of Ezekiel Harper.

Fri, 01/30/2015 - 4:30am
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Autosomal and Y-STR analysis of degraded DNA from the 120-year-old skeletal remains of Ezekiel Harper.

Forensic Sci Int Genet. 2014 Mar;9:33-41

Authors: Ambers A, Gill-King H, Dirkmaat D, Benjamin R, King J, Budowle B

Abstract
The 120-year-old skeletal remains of Confederate Civil War soldier Captain Ezekiel "Zeke" Harper were exhumed by court order in January 2011 for DNA analysis. The goal of the DNA testing was to support or refute whether Captain Harper had fathered a son (Earl J. Maxwell) with his Native American maid prior to his murder in 1892. Bones with adequate structural integrity (left tibia, right tibia, right femur, mandible, four teeth) were retrieved from the burial site and sent to the Institute of Applied Genetics in Fort Worth, Texas for analysis. Given the age and condition of the remains, three different extraction methods were used to maximize the probability of DNA recovery. The majority of the DNA isolates from over fifty separate bone sections yielded partial autosomal STR genotypes and partial Y-STR haplotypes. After comparing the partial results for concordance, consensus profiles were generated for comparison to reference samples from alleged family members. Considering the genetic recombination that occurs in autosomal DNA over the generations within a family, Y-STR analysis was determined to be the most appropriate and informative approach for determining potential kinship. Two of Earl J. Maxwell's grandsons submitted buccal samples for comparison. The Y-STR haplotypes obtained from both of these reference samples were identical to each other and to the alleles in Ezekiel Harper's consensus profile at all 17 loci examined. This Y-STR haplotype was not found in either of two major Y-STR population databases (U.S. Y-STR database and YHRD). The fact that the Y-STR haplotype obtained from Ezekiel's skeletal remains and Earl's grandsons is not found in either population database demonstrates its rarity and further supports a paternal lineage relationship among them. Results of the genetic analyses are consistent with the hypothesis that Earl J. Maxwell is the son of Ezekiel Harper.

PMID: 24528577 [PubMed - indexed for MEDLINE]

Neuroglobin Overexpression Inhibits AMPK Signaling and Promotes Cell Anabolism.

Wed, 01/28/2015 - 4:30am
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Neuroglobin Overexpression Inhibits AMPK Signaling and Promotes Cell Anabolism.

Mol Neurobiol. 2015 Jan 24;

Authors: Cai B, Li W, Mao X, Winters A, Ryou MG, Liu R, Greenberg DA, Wang N, Jin K, Yang SH

Abstract
Neuroglobin (Ngb) is a recently discovered globin with preferential localization to neurons. Growing evidence indicates that Ngb has distinct physiological functions separate from the oxygen storage and transport roles of other globins, such as hemoglobin and myoglobin. We found increased ATP production and decreased glycolysis in Ngb-overexpressing immortalized murine hippocampal cell line (HT-22), in parallel with inhibition of AMP-activated protein kinase (AMPK) signaling and activation of acetyl-CoA carboxylase (ACC). In addition, lipid and glycogen content was increased in Ngb-overexpressing HT-22 cells. AMPK signaling was also inhibited in the brain and heart from Ngb-overexpressing transgenic mice. Although Ngb overexpression did not change glycogen content in whole brain, glycogen synthase was activated in cortical neurons of Ngb-overexpressing mouse brain and Ngb overexpression primary neurons. Moreover, lipid and glycogen content was increased in hearts derived from Ngb-overexpressing mice. These findings suggest that Ngb functions as a metabolic regulator and enhances cellular anabolism through the inhibition of AMPK signaling.

PMID: 25616953 [PubMed - as supplied by publisher]

The unique protein kinase Cη: implications for breast cancer (review).

Wed, 01/28/2015 - 4:30am
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The unique protein kinase Cη: implications for breast cancer (review).

Int J Oncol. 2014 Aug;45(2):493-8

Authors: Pal D, Basu A

Abstract
Deregulation of key signal transduction pathways that govern important cellular processes leads to cancer. The development of effective therapeutics for cancer warrants a comprehensive understanding of the signaling pathways that are deregulated in cancer. The protein kinase C (PKC) family has served as an attractive target for cancer therapy for decades owing to its crucial roles in several cellular processes. PKCη is a novel member of the PKC family that plays critical roles in various cellular processes such as growth, proliferation, differentiation and cell death. The regulation of PKCη appears to be unique compared to other PKC isozymes, and there are conflicting reports regarding its role in cancer. This review focuses on the unique aspects of PKCη in terms of its structure, regulation and subcellular distribution and speculates on how these features could account for its distinct functions. We have also discussed the functional implications of PKCη in cancer with particular emphasis on breast cancer.

PMID: 24841225 [PubMed - indexed for MEDLINE]

STAT3 and its Phosphorylation are Involved in HIV-1 Tat-induced Transactivation of Glial Fibrillary Acidic Protein.

Tue, 01/27/2015 - 4:31am

STAT3 and its Phosphorylation are Involved in HIV-1 Tat-induced Transactivation of Glial Fibrillary Acidic Protein.

Curr HIV Res. 2015 Jan 20;

Authors: Fan Y, Timani KA, He JJ

Abstract
Human immunodeficiency virus type 1 (HIV-1) Tat protein is a major pathogenic factor in HIV-associated neurological diseases; it exhibits direct neurotoxicity and indirect astrocyte-mediated neurotoxicity. We have shown that Tat alone is capable of activating glial fibrillary acidic protein (GFAP) expression and inducing astrocytosis involving sequential activation of early growth response protein 1 (Egr-1) and p300. In this study, we determined the roles of signal transducer and activator of transcription 3 (STAT3) in Tat-induced GFAP transactivation. STAT3 expression and phosphorylation led to significant increases in GFAP transcription and protein expression. Tat expression was associated with increased STAT3 expression and phosphorylation in Tat-expressing astrocytes and HIV-infected astrocytes. GFAP, Egr-1 and p300 transcription and protein expression all showed positive response to STAT3 and its phosphorylation. Importantly, knockdown of STAT3 resulted in significant decreases in Tat-induced GFAP and Egr-1 transcription and protein expression. Taken together, these findings show that STAT3 is involved in and acts upstream of Egr1 and p300 in the Tat-induced GFAP transactivation cascade and suggest important roles of STAT3 in controlling astrocyte proliferation and activation in the HIV-infected central nervous system.

PMID: 25613134 [PubMed - as supplied by publisher]

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