Recent Research Articles from UNTHSC

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NCBI: db=pubmed; Term="University of North Texas Health Science Center"[All Fields] OR "Univ. of North Texas Health Science Center"[All Fields] OR "UNT Health Science Center"[All Fields] OR "Osteopathic Research Center"[All Fields] OR "University of North Texas System College of Pharmacy"[All Fields] OR "UNT System College of Pharmacy"[All Fields] OR "College of Pharmacy, University of North Texas System"[All Fields]
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Circulating mitochondrial DNA and Toll-like receptor 9 are associated with vascular dysfunction in spontaneously hypertensive rats.

Wed, 05/25/2016 - 06:38
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Circulating mitochondrial DNA and Toll-like receptor 9 are associated with vascular dysfunction in spontaneously hypertensive rats.

Cardiovasc Res. 2015 Jul 1;107(1):119-30

Authors: McCarthy CG, Wenceslau CF, Goulopoulou S, Ogbi S, Baban B, Sullivan JC, Matsumoto T, Webb RC

Abstract
AIMS: Immune system activation is a common feature of hypertension pathogenesis. However, the mechanisms that initiate this activation are not well understood. Innate immune system recognition and response to danger are becoming apparent in many cardiovascular diseases. Danger signals can arise from not only pathogens, but also damage-associated molecular patterns (DAMPs). Our first hypothesis was that the DAMP, mitochondrial DNA (mtDNA), which is recognized by Toll-like receptor 9 (TLR9), is elevated in the circulation of spontaneously hypertensive rats (SHR), and that the deoxyribonuclease enzymes responsible for its degradation have decreased activity in SHR. Based on these novel SHR phenotypes, we further hypothesized that (i) treatment of SHR with an inhibitory oligodinucleotide for TLR9 (ODN2088) would lower blood pressure and that (ii) treatment of normotensive rats with a TLR9-specific CpG oligonucleotide (ODN2395) would cause endothelial dysfunction and increase blood pressure.
METHODS AND RESULTS: We observed that SHR have elevated circulating mtDNA and diminished deoxyribonuclease I and II activity. Additionally, treatment of SHR with ODN2088 lowered systolic blood pressure. On the other hand, treatment of normotensive rats with ODN2395 increased systolic blood pressure and rendered their arteries less sensitive to acetylcholine-induced relaxation and more sensitive to norepinephrine-induced contraction. This dysfunctional vasoreactivity was due to increased cyclooxygenase and p38 mitogen-activated protein kinase activation, increased reactive oxygen species generation, and reduced nitric oxide bioavailability.
CONCLUSION: Circulating mtDNA and impaired deoxyribonuclease activity may lead to the activation of the innate immune system, via TLR9, and contribute to elevated arterial pressure and vascular dysfunction in SHR.

PMID: 25910936 [PubMed - indexed for MEDLINE]

Assessment of subunit-dependent direct gating and allosteric modulatory effects of carisoprodol at GABA(A) receptors.

Wed, 05/25/2016 - 06:38
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Assessment of subunit-dependent direct gating and allosteric modulatory effects of carisoprodol at GABA(A) receptors.

Neuropharmacology. 2015 Oct;97:414-25

Authors: Kumar M, González LA, Dillon GH

Abstract
Carisoprodol is a widely prescribed muscle relaxant, abuse of which has grown considerably in recent years. It directly activates and allosterically modulates α1β2γ2 GABAARs, although the site(s) of action are unknown. To gain insight into the actions of carisoprodol, subunit-dependent effects of this drug were assessed. Whole-cell patch clamp recordings were obtained from HEK293 cells expressing α1β2, α1β3 or αxβzγ2 (where x = 1-6 and z = 1-3) GABAARs, and in receptors incorporating the δ subunit (modeling extrasynaptic receptors). The ability to directly gate and allosterically potentiate GABA-gated currents was observed for all configurations. Presence or absence of the γ2 subunit did not affect the ability of carisoprodol to directly gate or allosterically modulate the receptor. Presence of the β1 subunit conferred highest efficacy for direct activation relative to maximum GABA currents, while presence of the β2 subunit conferred highest efficacy for allosteric modulation of the GABA response. With regard to α subunits, carisoprodol was most efficacious at enhancing the actions of GABA in receptors incorporating the α1 subunit. The ability to directly gate the receptor was generally comparable regardless of the α subunit isoform, although receptors incorporating the α3 subunit showed significantly reduced direct gating efficacy and affinity. In extrasynaptic (α1β3δ and α4β3δ) receptors, carisoprodol had greater efficacy than GABA as a direct gating agonist. In addition, carisoprodol allosterically potentiated both EC20 and saturating GABA concentrations in these receptors. In assessing voltage-dependence, we found direct gating and inhibitory effects were insensitive to membrane voltage, whereas allosteric modulatory effects were affected by membrane voltage. Our findings demonstrate direct and allosteric effects of carisoprodol at synaptic and extrasynpatic GABAARs and that subunit isoform influences these effects.

PMID: 25896767 [PubMed - indexed for MEDLINE]

The effects of sigma (σ1) receptor-selective ligands on muscarinic receptor antagonist-induced cognitive deficits in mice.

Wed, 05/25/2016 - 06:38
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The effects of sigma (σ1) receptor-selective ligands on muscarinic receptor antagonist-induced cognitive deficits in mice.

Br J Pharmacol. 2015 May;172(10):2519-31

Authors: Malik M, Rangel-Barajas C, Sumien N, Su C, Singh M, Chen Z, Huang RQ, Meunier J, Maurice T, Mach RH, Luedtke RR

Abstract
BACKGROUND AND PURPOSE: Cognitive deficits in patients with Alzheimer's disease, Parkinson's disease, traumatic brain injury and stroke often involve alterations in cholinergic signalling. Currently available therapeutic drugs provide only symptomatic relief. Therefore, novel therapeutic strategies are needed to retard and/or arrest the progressive loss of memory.
EXPERIMENTAL APPROACH: Scopolamine-induced memory impairment provides a rapid and reversible phenotypic screening paradigm for cognition enhancement drug discovery. Male C57BL/6J mice given scopolamine (1 mg·kg(-1) ) were used to evaluate the ability of LS-1-137, a novel sigma (σ1) receptor-selective agonist, to improve the cognitive deficits associated with muscarinic antagonist administration.
KEY RESULTS: LS-1-137 is a high-affinity (Ki = 3.2 nM) σ1 receptor agonist that is 80-fold selective for σ1, compared with σ2 receptors. LS-1-137 binds with low affinity at D2-like (D2, D3 and D4) dopamine and muscarinic receptors. LS-1-137 was found to partially reverse the learning deficits associated with scopolamine administration using a water maze test and an active avoidance task. LS-1-137 treatment was also found to trigger the release of brain-derived neurotrophic factor from rat astrocytes.
CONCLUSIONS AND IMPLICATIONS: The σ1 receptor-selective compound LS-1-137 may represent a novel candidate cognitive enhancer for the treatment of muscarinic receptor-dependent cognitive deficits.

PMID: 25573298 [PubMed - indexed for MEDLINE]

A comparative evaluation of treatments with 17β-estradiol and its brain-selective prodrug in a double-transgenic mouse model of Alzheimer's disease.

Tue, 05/24/2016 - 06:30

A comparative evaluation of treatments with 17β-estradiol and its brain-selective prodrug in a double-transgenic mouse model of Alzheimer's disease.

Horm Behav. 2016 May 19;

Authors: Tschiffely AE, Schuh RA, Prokai-Tatrai K, Prokai L, Ottinger MA

Abstract
Estrogens are neuroprotective and, thus, potentially useful for the therapy of Alzheimer's disease; however, clinical use of hormone therapy remains controversial due to adverse peripheral effects. The goal of this study was to investigate the benefits of treatment with 10β,17β-dihydroxyestra-1.4-dien-3-one (DHED), a brain-selective prodrug of 17β-estradiol, in comparison with the parent hormone using APPswe/PS1dE9 double transgenic mice to model the pathology of the disease. Ovariectomized and intact females were continuously treated with vehicle, 17β-estradiol, or DHED via subcutaneous osmotic pumps from 6 to 8months of age. We confirmed that this prolonged treatment with DHED did not stimulate uterine tissue, whereas 17β-estradiol treatment increased uterine weight. Amyloid precursor protein decreased in both treatment groups of intact, but not in ovariectomized double transgenic females in which ovariectomy already decreased the expression of this protein significantly. However, reduced brain amyloid-β peptide levels could be observed for both treatments. Consequently, double-transgenic ovariectomized and intact mice had higher cognitive performance compared to untreated control animals in response to both estradiol and DHED administrations. Overall, the tested brain-selective 17β-estradiol prodrug proved to be an effective early-stage intervention in an Alzheimer's disease-relevant mouse model without showing systemic impact and, thus, warrants further evaluation as a potential therapeutic candidate.

PMID: 27210479 [PubMed - as supplied by publisher]

Disulfide cross-linked micelles of novel HDAC inhibitor thailandepsin A for the treatment of breast cancer.

Tue, 05/24/2016 - 06:30
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Disulfide cross-linked micelles of novel HDAC inhibitor thailandepsin A for the treatment of breast cancer.

Biomaterials. 2015 Oct;67:183-93

Authors: Xiao K, Li YP, Wang C, Ahmad S, Vu M, Kuma K, Cheng YQ, Lam KS

Abstract
Histone deacetylase (HDAC) inhibitors are an emerging class of targeted therapy against cancers. Thailandepsin A (TDP-A) is a recently discovered class I HDAC inhibitor with broad anti-proliferative activities. In the present study, we aimed to investigate the potential of TDP-A in the treatment of breast cancer. We demonstrated that TDP-A inhibited cell proliferation and induced apoptosis in breast cancer cells at low nanomolar concentrations. TDP-A activated the intrinsic apoptotic pathway through increase of pro-apoptotic protein Bax, decrease of anti-apoptotic Bcl-2, and cleavage of caspase-3 and poly (ADP-ribose) polymerase (PARP). TDP-A also induced cell cycle arrest at the G2/M phase, and promoted the production of reactive oxygen species (ROS). We have successfully encapsulated TDP-A into our recently developed disulfide cross-linked micelles (DCMs), improving its water solubility and targeted delivery. TDP-A loaded DCMs (TDP-A/DCMs) possess the characteristics of high loading capacity (>20%, w/w), optimal and monodisperse particle size (16 ± 4 nm), outstanding stability with redox stimuli-responsive disintegration, sustained drug release, and preferential uptake in breast tumors. In the MDA-MB-231 breast cancer xenograft model, TDP-A/DCMs were more efficacious than the FDA-approved FK228 at well-tolerated doses. Furthermore, TDP-A/DCMs exhibited synergistic anticancer effects when combined with the proteasome inhibitor bortezomib (BTZ) loaded DCMs (BTZ/DCMs). Our results indicate that TDP-A nanoformulation alone or in combination with BTZ nanoformulation are efficacious against breast cancer.

PMID: 26218744 [PubMed - indexed for MEDLINE]

Severe hypercholesterolemia and liver disease in a 3-year old.

Sun, 05/22/2016 - 06:30

Severe hypercholesterolemia and liver disease in a 3-year old.

J Clin Lipidol. 2016 May-Jun;10(3):650-3

Authors: Patel AM, Brautbar A, Desai NK, Wilson DP

Abstract
Lipoprotein-X, which is composed of phospholipids and non-esterified cholesterol, is an abnormal lipoprotein with a density range similar to LDL-C. The two most common ways which lipoprotein-X accumulates is from reflux of bile salts into plasma or deficiency in lecithin cholesterol acyltransferase. This is a case of severe hypercholesterolemia and liver disease in a 3- year old male that presented with pruritus, pale stool, scleral ictus, and abdominal distention. He was diagnosed with primary sclerosing cholangitis which was confirmed by liver biopsy. Our patient was treated with steroids and immunomodulator therapy which was associated with significant reduction in cholestasis and LDL-C levels. Lipoprotein-X has several properties that make it anti-atherogenic, which raises the question if treatment for hypercholesterolemia should be initiated.

PMID: 27206954 [PubMed - in process]

AMBULATORY BLOOD PRESSURE PATTERNS IN PATIENTS WITH RETINAL VEIN OCCLUSION.

Sat, 05/21/2016 - 06:38

AMBULATORY BLOOD PRESSURE PATTERNS IN PATIENTS WITH RETINAL VEIN OCCLUSION.

Retina. 2016 May 19;

Authors: Rao VN, Ulrich JN, Viera AJ, Parlin A, Fekrat S, Chavala SH

Abstract
PURPOSE: Failure of blood pressure (BP) to dip during sleep (nondipper pattern) is associated with cardiovascular disease and stroke. The prevalence and degree of nondipping and masked hypertension in patients with retinal vein occlusion (RVO), which is associated with stroke, has not been previously examined.
METHODS: We measured clinic and 24-hour ambulatory BPs in 22 patients with RVO and 20 control participants without known eye disease matched by age and sex. Mean BP dipping, defined as the ratio of difference in mean awake and sleep systolic BPs to mean awake systolic BP, and masked and nocturnal hypertension were compared between groups.
RESULTS: Mean 24-hour ambulatory BP was 144/79 mmHg among those with RVO and 136/77 mmHg among controls. Patients with RVO had an almost 2-fold higher prevalence of nondipping pattern (80.8% [95% confidence interval, 52.8-94.1] vs. 50.4% [95% confidence interval, 26.1-74.5]; P = 0.008). Average sleep systolic BP dip in patients with RVO was 6.1% versus 11.9% in controls (P = 0.004). More patients with RVO had masked hypertension by ambulatory BPs than controls (71% vs. 50%), but this difference was not statistically significant.
CONCLUSION: Our data suggest an association between RVO and nondipper BP pattern. Ambulatory BP monitoring may be useful in the evaluation of patients with RVO by identifying those who may benefit from more aggressive BP control.

PMID: 27205892 [PubMed - as supplied by publisher]

Elevated Atmospheric Levels of Benzene and Benzene-Related Compounds from Unconventional Shale Extraction and Processing: Human Health Concern for Residential Communities.

Sat, 05/21/2016 - 06:38

Elevated Atmospheric Levels of Benzene and Benzene-Related Compounds from Unconventional Shale Extraction and Processing: Human Health Concern for Residential Communities.

Environ Health Insights. 2016;10:75-82

Authors: Rich AL, Orimoloye HT

Abstract
BACKGROUND: The advancement of natural gas (NG) extraction across the United States (U.S.) raises concern for potential exposure to hazardous air pollutants (HAPs). Benzene, a HAP and a primary chemical of concern due to its classification as a known human carcinogen, is present in petroleum-rich geologic formations and is formed during the combustion of bypass NG. It is a component in solvents, paraffin breakers, and fuels used in NG extraction and processing (E&P).
OBJECTIVES: The objectives of this study are to confirm the presence of benzene and benzene-related compounds (benzene[s]) in residential areas, where unconventional shale E&P is occurring, and to determine if benzene[s] exists in elevated atmospheric concentrations when compared to national background levels.
METHODS: Ambient air sampling was conducted in six counties in the Dallas/Fort Worth Metroplex with passive samples collected in evacuated 6-L Summa canisters. Samples were analyzed by gas chromatography/mass spectrometry, with sampling performed at variable distances from the facility fence line.
RESULTS: Elevated concentrations of benzene[s] in the atmosphere were identified when compared to U.S. Environmental Protection Agency's Urban Air Toxics Monitoring Program. The 24-hour benzene concentrations ranged from 0.6 parts per billion by volume (ppbv) to 592 ppbv, with 1-hour concentrations from 2.94 ppbv to 2,900.20 ppbv.
CONCLUSION: Benzene is a known human carcinogen capable of multisystem health effects. Exposure to benzene is correlated with bone marrow and blood-forming organ damage and immune system depression. Sensitive populations (children, pregnant women, elderly, immunocompromised) and occupational workers are at increased risk for adverse health effects from elevated atmospheric levels of benzene[s] in residential areas with unconventional shale E&P.

PMID: 27199565 [PubMed]

Survival Analysis Following Extracorporeal Membrane Oxygenation in Critically Ill Adults: A Nationwide Cohort Study.

Sat, 05/21/2016 - 06:38

Survival Analysis Following Extracorporeal Membrane Oxygenation in Critically Ill Adults: A Nationwide Cohort Study.

Circulation. 2016 May 19;

Authors: Chang CH, Chen HC, Caffrey JL, Hsu J, Lin JW, Lai MS, Chen YS

Abstract
BACKGROUND: -Extracorporeal membrane oxygenation (ECMO) provides circulatory and respiratory support for patients with severe acute cardiopulmonary failure. The objective of this study was to examine the survival outcomes for patients who received ECMO.
METHODS AND RESULTS: -Adult patients who received ECMO from September 1, 2002 to December 31, 2012 were identified from Taiwan's National Health Insurance Database associated with 1) coronary artery bypass surgery (CABG), 2) myocardial infarction/cardiogenic shock (MI/CS), 3) injury, and 4) infection/septic shock (Infection). A Cox-regression model was used to determine hazard ratios (HR) and compare 30-day and one-year survival rates using the MI/CS group as the reference. The mean age and standard deviation of the 4,227 patient cohort was 57±17 years and 72% were male. The overall mortalities were 59.8% and 76.5% at one month and one year. Survival statistics deteriorated sharply when ECMO was required for more than 3 days. Acute (30-day) survival was more favorable in the Infection (n = 1,076, HR: 0.61, 95% CI: 0.55-0.67), CABG (n = 1,077, HR: 0.68 [0.61-0.75]), and Injury (n = 369, HR: 0.82 [0.70-0.95]) groups. The extended survival rapidly approached an asymptote near 20% for the Infection, MI/CS (n = 1,705), and CABG groups. The pattern of survival for the injury group was somewhat better, exceeding 30% at yearend.
CONCLUSIONS: -Regardless of initial pathology, patients requiring ECMO were critically ill with similar guarded prognoses. Those in the trauma group had somewhat better outcomes. Determining the efficacy and cost-effectiveness of ECMO should be a critical future goal.

PMID: 27199466 [PubMed - as supplied by publisher]

DNA methylation of oxidative stress genes and cancer risk in the Normative Aging Study.

Wed, 05/18/2016 - 14:30
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DNA methylation of oxidative stress genes and cancer risk in the Normative Aging Study.

Am J Cancer Res. 2016;6(2):553-61

Authors: Gao T, Joyce BT, Liu L, Zheng Y, Dai Q, Zhang Z, Zhang W, Shrubsole MJ, Tao MH, Schwartz J, Baccarelli A, Hou L

Abstract
Oxidative stress (OS) is a primary mechanism of carcinogenesis, and methylation of genes related to it may play a role in cancer development. In this study, we examined the prospective association between blood DNA methylation of four oxidative stress genes and cancer incidence. Our study population included a total of 582 participants in the Normative Aging Study (NAS) who had blood drawn during 1-4 visits from 1999-2012 (mean follow up 9.0 years). Promoter DNA methylation of CRAT, iNOS, OGG1 and GCR in blood leukocytes was measured using pyrosequencing. We used Cox regression models to examine prospective associations between cancer incidence and both methylation at the baseline visit and methylation rate of changes over time. Baseline OGG1 methylation was associated with higher risk of all-cancer (HR: 1.43, 95% CI: 1.15-1.78) and prostate cancer (HR: 1.52, 95% CI: 1.03-2.25) incidence. Compared with participants remaining cancer-free, those who eventually developed cancer had significantly accelerated CRAT methylation (p = 0.04) and decelerated iNOS methylation (p<0.01) over time prior to cancer diagnosis. Accelerated CRAT methylation was associated with higher all-cancer incidence (HR: 3.88, 95% CI: 1.06-14.30), whereas accelerated iNOS methylation was associated with lower all-cancer incidence (HR: 0.08, 95% CI 0.02-0.38). Our results suggest that methylation and its dynamic change over time in OS-related genes, including OGG1, CRAT and iNOS, may play an important role in carcinogenesis. These results can potentially facilitate the development of early detection biomarkers and new treatments for a variety of cancers.

PMID: 27186424 [PubMed]

Novel Y-chromosome Short Tandem Repeat Variants Detected Through the Use of Massively Parallel Sequencing.

Wed, 05/18/2016 - 14:30
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Novel Y-chromosome Short Tandem Repeat Variants Detected Through the Use of Massively Parallel Sequencing.

Genomics Proteomics Bioinformatics. 2015 Aug;13(4):250-7

Authors: Warshauer DH, Churchill JD, Novroski N, King JL, Budowle B

Abstract
Massively parallel sequencing (MPS) technology is capable of determining the sizes of short tandem repeat (STR) alleles as well as their individual nucleotide sequences. Thus, single nucleotide polymorphisms (SNPs) within the repeat regions of STRs and variations in the pattern of repeat units in a given repeat motif can be used to differentiate alleles of the same length. In this study, MPS was used to sequence 28 forensically-relevant Y-chromosome STRs in a set of 41 DNA samples from the 3 major U.S. population groups (African Americans, Caucasians, and Hispanics). The resulting sequence data, which were analyzed with STRait Razor v2.0, revealed 37 unique allele sequence variants that have not been previously reported. Of these, 19 sequences were variations of documented sequences resulting from the presence of intra-repeat SNPs or alternative repeat unit patterns. Despite a limited sampling, two of the most frequently-observed variants were found only in African American samples. The remaining 18 variants represented allele sequences for which there were no published data with which to compare. These findings illustrate the great potential of MPS with regard to increasing the resolving power of STR typing and emphasize the need for sample population characterization of STR alleles.

PMID: 26391384 [PubMed - indexed for MEDLINE]

Regulatory CD4+CD25+ T Cells Dampen Inflammatory Disease in Murine Mycoplasma Pneumonia and Promote IL-17 and IFN-γ Responses.

Sat, 05/14/2016 - 06:36

Regulatory CD4+CD25+ T Cells Dampen Inflammatory Disease in Murine Mycoplasma Pneumonia and Promote IL-17 and IFN-γ Responses.

PLoS One. 2016;11(5):e0155648

Authors: Odeh AN, Simecka JW

Abstract
Mycoplasmas cause respiratory diseases characterized by persistent infection and chronic airway inflammation. Mycoplasma lung disease is immunopathologic, with CD4+ Th cells determining both disease severity and resistance to infection. Th2 cell responses promote immunopathology, while Th1 cells confer resistance to infection. However, regulatory CD4+ T cells may also have a role in the pathogenesis of mycoplasma respiratory diseases. We hypothesized Treg cells control the severity of the inflammatory lesions and may also promote persistence of infection. To examine this, BALB/c mice were depleted of CD25+ cells, and had increased disease severity due to Mycoplasma pulmonis infection. Increases in mycoplasma antibody responses and lymphocyte infiltration into lungs also occurred after CD25+ cell depletion. CD4+CD25+ regulatory T cells promoted IFN-γ and IL-17 mycoplasma-specific CD4+ T cell responses in vitro and in vivo, while dampening IL-13+ Th responses. Neither IL-10 nor TGF-ß expression was detected in CD4+CD25+ T cells from lymph nodes. Thus, a regulatory T cell population plays an important role in controlling damaging immune responses in mycoplasma respiratory disease but does not contribute to persistence of infection. It appears that a regulatory T cell population preferentially dampens Th2 cell-mediated inflammatory responses to mycoplasma through a mechanism independent of IL-10 or TGF-ß characteristic of "classic" Treg cells.

PMID: 27175511 [PubMed - as supplied by publisher]

Exosome-associated release, uptake, and neurotoxicity of HIV-1 Tat protein.

Sat, 05/14/2016 - 06:36

Exosome-associated release, uptake, and neurotoxicity of HIV-1 Tat protein.

J Neurovirol. 2016 May 12;

Authors: Rahimian P, He JJ

Abstract
HIV-1 Tat is an indispensible transactivator for HIV gene transcription and replication. It has been shown to exit cells as a free protein and enter neighboring cells or interact with surface receptors of neighboring cells to regulate gene expression and cell function. In this study, we report, for the first time, exosome-associated Tat release and uptake. Using a HIV-1 LTR-driven luciferase reporter-based cell assay and Western blotting or in combination with exosome inhibitor, OptiPrep gradient fractionation, and exosome depletion, we demonstrated significant presence of HIV-1 Tat in exosomes derived from Tat-expressing primary astrocytes, Tat-transfected U373.MG and 293T, and HIV-infected MT4. We further showed that exosome-associated Tat from Tat-expressing astrocytes was capable of causing neurite shortening and neuron death, further supporting that this new form of extracellular Tat is biologically active. Lastly, we constructed a Tat mutant deleted of its basic domain and determined the role of the basic domain in Tat trafficking into exosomes. Basic domain-deleted Tat exhibited no apparent effects on Tat trafficking into exosomes, while maintained its dominant-negative function in Tat-mediated LTR transactivation. Taken together, these results show a significant fraction of Tat is secreted and present in the form of exosomes and may contribute to the stability of extracellular Tat and broaden the spectrum of its target cells.

PMID: 27173397 [PubMed - as supplied by publisher]

The Risks to Patient Privacy from Publishing Data from Clinical Anesthesia Studies.

Sat, 05/14/2016 - 06:36

The Risks to Patient Privacy from Publishing Data from Clinical Anesthesia Studies.

Anesth Analg. 2016 May 11;

Authors: O'Neill L, Dexter F, Zhang N

Abstract
In this article, we consider the privacy implications of posting data from small, randomized trials, observational studies, or case series in anesthesia from a few (e.g., 1-3) hospitals. Prior to publishing such data as supplemental digital content, the authors remove attributes that could be used to re-identify individuals, a process known as "anonymization." Posting health information that has been properly "de-identified" is assumed to pose no risks to patient privacy. Yet, computer scientists have demonstrated that this assumption is flawed. We consider various realistic scenarios of how the publication of such data could lead to breaches of patient privacy. Several examples of successful privacy attacks are reviewed, as well as the methods used. We survey the latest models and methods from computer science for protecting health information and their application to posting data from small anesthesia studies. To illustrate the vulnerability of such published data, we calculate the "population uniqueness" for patients undergoing one or more surgical procedures using data from the State of Texas. For a patient selected uniformly at random, the probability that an adversary could match this patient's record to a unique record in the state external database was 42.8% (SE < 0.1%). Despite the 42.8% being an unacceptably high level of risk, it underestimates the risk for patients from smaller states or provinces. We propose an editorial policy that greatly reduces the likelihood of a privacy breach, while supporting the goal of transparency of the research process.

PMID: 27172145 [PubMed - as supplied by publisher]

Constrictor prostanoids and uridine adenosine tetraphosphate: vascular mediators and therapeutic targets in hypertension and diabetes.

Sat, 05/14/2016 - 06:36
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Constrictor prostanoids and uridine adenosine tetraphosphate: vascular mediators and therapeutic targets in hypertension and diabetes.

Br J Pharmacol. 2015 Aug;172(16):3980-4001

Authors: Matsumoto T, Goulopoulou S, Taguchi K, Tostes RC, Kobayashi T

Abstract
Vascular dysfunction plays a pivotal role in the development of systemic complications associated with arterial hypertension and diabetes. The endothelium, or more specifically, various factors derived from endothelial cells tightly regulate vascular function, including vascular tone. In physiological conditions, there is a balance between endothelium-derived factors, that is, relaxing factors (endothelium-derived relaxing factors; EDRFs) and contracting factors (endothelium-derived contracting factors; EDCFs), which mediate vascular homeostasis. However, in disease states, such as diabetes and arterial hypertension, there is an imbalance between EDRF and EDCF, with a reduction of EDRF signalling and an increase of EDCF signalling. Among EDCFs, COX-derived vasoconstrictor prostanoids play an important role in the development of vascular dysfunction associated with hypertension and diabetes. Moreover, uridine adenosine tetraphosphate (Up4 A), identified as an EDCF in 2005, also modulates vascular function. However, the role of Up4 A in hypertension- and diabetes-associated vascular dysfunction is unclear. In the present review, we focused on experimental and clinical evidence that implicate these two EDCFs (vasoconstrictor prostanoids and Up4 A) in vascular dysfunction associated with hypertension and diabetes.

PMID: 26031319 [PubMed - indexed for MEDLINE]

Identification and localization of lamina cribrosa cells in the human optic nerve head.

Thu, 05/12/2016 - 06:30

Identification and localization of lamina cribrosa cells in the human optic nerve head.

Exp Eye Res. 2016 May 7;

Authors: Tovar-Vidales T, Wordinger RJ, Clark AF

Abstract
One of the central features of glaucoma is progressive cupping and excavation of the optic nerve head (ONH). Unmyelinated retinal ganglion cell (RGC) axons exit the eye through the ONH, which is supported by the lamina cribrosa (LC) consisting of plates of connective tissue with channels for bundles of RGC axons. The LC progressively remodels during glaucoma, but the cellular and molecular mechanisms responsible for this remodeling are poorly understood. Two major cell types have been isolated and cultured from the human ONH, which differ in their characteristics. Glial fibrillary acidic protein (GFAP) positive ONH astrocytes are the major cell type and are reactive in glaucoma. GFAP negative LC cells are the second major cell type isolated from the human ONH, and in contrast to ONH astrocytes, are α-smooth muscle actin (α-SMA) positive. Although a number of in vitro studies have been conducted with LC cells, to date there has been no direct evidence for these cells in situ in the human ONH. We used GFAP and α-SMA immunofluorescent staining of human eyes to clearly demonstrate the presence of not only ONH astrocytes within the human ONH, but also LC cells within the cribriform (e.g. laminar) plates/beams of the LC region. Both of these cell types likely play important roles in the homeostatic maintenance of the ONH and pathogenic changes that occur in primary open angle glaucoma (POAG).

PMID: 27167365 [PubMed - as supplied by publisher]

Human trabecular meshwork cells express BMP antagonist mRNAs and proteins.

Thu, 05/12/2016 - 06:30

Human trabecular meshwork cells express BMP antagonist mRNAs and proteins.

Exp Eye Res. 2016 May 7;

Authors: Tovar-Vidales T, Fitzgerald AM, Clark AF

Abstract
Glaucoma patients have elevated aqueous humor and trabecular meshwork (TM) levels of transforming growth factor-beta2 (TGF-β2). TGF-β2 has been associated with increased extracellular matrix (ECM) deposition (i.e. fibronectin), which is attributed to the increased resistance of aqueous humor outflow through the TM. We have previously demonstrated that bone morphogenetic protein (BMP) 4 selectively counteracts the profibrotic effect of TGF-β2 with respect to ECM synthesis in the TM, and this action is reversed by the BMP antagonist gremlin. Thus, the BMP and TGF-β signaling pathways antagonize each other's antifibrotic and profibrotic roles. The purpose of this study was to determine whether cultured human TM cells: (a) express other BMP antagonists noggin, chordin, BMPER, BAMBI, Smurf1 and 2, and (b) whether expression of these proteins is regulated by exogenous TGF-β2 treatment. Primary human trabecular meshwork (TM) cells were grown to confluency and treated with TGF-β2 (5 ng/ml) for 24 or 48 h in serum-free medium. Untreated cell served as controls. qPCR and Western immunoblots (WB) determined that human TM cells expressed mRNAs and proteins for the BMP antagonists proteins: noggin, chordin, BMPER, BAMBI, and Smurf1/2. Exogenous TGF-β2 decreased chordin, BMPER, BAMBI, and Smurf1 mRNA and protein expression. In contrast, TGF-β2 increased secreted noggin and Smurf2 mRNA and protein levels. BMP antagonist members are expressed in the human TM. These molecules may be involved in the normal function of the TM as well as TM pathogenesis. Altered expression of BMP antagonist members may lead to functional changes in the human TM.

PMID: 27167364 [PubMed - as supplied by publisher]

Letter to the Editor: comments on biostatistical power of sibling analysis by STR markers.

Thu, 05/12/2016 - 06:30

Letter to the Editor: comments on biostatistical power of sibling analysis by STR markers.

Int J Legal Med. 2016 May 11;

Authors: Chakraborty R

PMID: 27166704 [PubMed - as supplied by publisher]

Molecular mechanisms of serotonergic action of the HIV-1 antiretroviral efavirenz.

Tue, 05/10/2016 - 06:33

Molecular mechanisms of serotonergic action of the HIV-1 antiretroviral efavirenz.

Pharmacol Res. 2016 May 5;

Authors: Dalwadi DA, Kim S, Amdani SM, Chen Z, Huang RQ, Schetz JA

Abstract
Efavirenz is highly effective at suppressing HIV-1, and the WHO guidelines list it as a component of the first-line antiretroviral (ARV) therapies for treatment-naïve patients. Though the pharmacological basis is unclear, efavirenz is commonly associated with a risk for neuropsychiatric adverse events (NPAEs) when taken at the prescribed dose. In many patients these NPAEs appear to subside after several weeks of treatment, though long-term studies show that in some patients the NPAEs persist. In a recent study focusing on the abuse potential of efavirenz, its receptor psychopharmacology was reported to include interactions with a number of established molecular targets for known drugs of abuse, and it displayed a prevailing behavioral profile in rodents resembling an LSD-like activity. In this report, we discovered interactions with additional serotonergic targets that may be associated with efavirenz-induced NPAEs. The most robust interactions were with 5-HT3A and 5-HT6 receptors, with more modest interactions noted for the 5-HT2B receptor and monoamine oxidase A. From a molecular mechanistic perspective, efavirenz acts as a 5-HT6 receptor inverse agonist of Gs-signaling, 5-HT2A and 5-HT2C antagonist of Gq-signaling, and a blocker of the 5-HT3A receptor currents. Efavirenz also completely or partially blocks agonist stimulation of the M1 and M3 muscarinic receptors, respectively. Schild analysis suggests that efavirenz competes for the same site on the 5-HT2A receptor as two known hallucinogenic partial agonists (±)-DOI and LSD. Prolonged exposure to efavirenz reduces 5-HT2A receptor density and responsiveness to 5-HT. Other ARVs such as zidovudine, nevirapine and emtricitabine did not share the same complex pharmacological profile as efavirenz, though some of them weakly interact with the 5-HT6 receptor or modestly block GABAA currents.

PMID: 27157251 [PubMed - as supplied by publisher]

Target engagement and drug residence time can be observed in living cells with BRET.

Tue, 05/10/2016 - 06:33
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Target engagement and drug residence time can be observed in living cells with BRET.

Nat Commun. 2015;6:10091

Authors: Robers MB, Dart ML, Woodroofe CC, Zimprich CA, Kirkland TA, Machleidt T, Kupcho KR, Levin S, Hartnett JR, Zimmerman K, Niles AL, Ohana RF, Daniels DL, Slater M, Wood MG, Cong M, Cheng YQ, Wood KV

Abstract
The therapeutic action of drugs is predicated on their physical engagement with cellular targets. Here we describe a broadly applicable method using bioluminescence resonance energy transfer (BRET) to reveal the binding characteristics of a drug with selected targets within intact cells. Cell-permeable fluorescent tracers are used in a competitive binding format to quantify drug engagement with the target proteins fused to Nanoluc luciferase. The approach enabled us to profile isozyme-specific engagement and binding kinetics for a panel of histone deacetylase (HDAC) inhibitors. Our analysis was directed particularly to the clinically approved prodrug FK228 (Istodax/Romidepsin) because of its unique and largely unexplained mechanism of sustained intracellular action. Analysis of the binding kinetics by BRET revealed remarkably long intracellular residence times for FK228 at HDAC1, explaining the protracted intracellular behaviour of this prodrug. Our results demonstrate a novel application of BRET for assessing target engagement within the complex milieu of the intracellular environment.

PMID: 26631872 [PubMed - indexed for MEDLINE]

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