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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Exposure to common respiratory bacteria alters the airway epithelial response to subsequent viral infection.

Sun, 06/05/2016 - 06:30

Exposure to common respiratory bacteria alters the airway epithelial response to subsequent viral infection.

Respir Res. 2016;17(1):68

Authors: Bellinghausen C, Gulraiz F, Heinzmann AC, Dentener MA, Savelkoul PH, Wouters EF, Rohde GG, Stassen FR

Abstract
BACKGROUND: Colonization of the airways with potential pathogenic bacteria is observed in a number of chronic respiratory diseases, such as COPD or cystic fibrosis. Infections with respiratory viruses are known triggers of exacerbations of these diseases. We here investigated if pre-exposure to bacteria alters the response of lung epithelial cells to subsequent viral infection.
METHODS: Bronchial epithelial cells (BEAS-2B cells and primary bronchial epithelial cells) were exposed to heat-inactivated Haemophilus influenzae, Pseudomonas aeruginosa or Streptococcus pneumoniae and subsequently infected with respiratory syncytial virus (RSV), type 2 human adenovirus or influenza B. Levels of pro-inflammatory cytokines, viral replication and expression of pattern recognition receptors were determined in culture supernatants and/or cell lysates.
RESULTS: Exposure of BEAS-2B cells to H. influenzae before and during RSV-infection synergistically increased the release of IL-6 (increase above calculated additive effect at 72 h: 56 % ± 3 %, mean ± SEM) and IL-8 (53 % ± 12 %). This effect was sustained even when bacteria were washed away before viral infection and was neither associated with enhanced viral replication, nor linked to increased expression of key pattern recognition receptors. P. aeruginosa enhanced the release of inflammatory cytokines to a similar extent, yet only if bacteria were also present during viral infection. S. pneumoniae did not enhance RSV-induced cytokine release. Surprisingly, adenovirus infection significantly reduced IL-6 release in cells exposed to either of the three tested bacterial strains by on average more than 50 %. Infection with influenza B on the other hand did not affect cytokine production in BEAS-2B cells exposed to the different bacterial strains.
CONCLUSION: Pre-exposure of epithelial cells to bacteria alters the response to subsequent viral infection depending on the types of pathogen involved. These findings highlight the complexity of microbiome interactions in the airways, possibly contributing to the susceptibility to exacerbations and the natural course of airway diseases.

PMID: 27259950 [PubMed - as supplied by publisher]

Bitropic D3 Dopamine Receptor Selective Compounds as Potential Antipsychotics.

Sat, 06/04/2016 - 06:34
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Bitropic D3 Dopamine Receptor Selective Compounds as Potential Antipsychotics.

Curr Pharm Des. 2015;21(26):3700-24

Authors: Luedtke RR, Rangel-Barajas C, Malik M, Reichert DE, Mach RH

Abstract
Neuropsychiatric disorders represent a substantial social and health care issue. The National Institutes of Health estimates that greater than 2 million adults suffer from neuropsychiatric disorders in the USA. These individuals experience symptoms that can include auditory hallucinations, delusions, unrealistic beliefs and cognitive dysfunction. Although antipsychotic medications are available, suboptimal therapeutic responses are observed for approximately one-third of patients. Therefore, there is still a need to explore new pharmacotherapeutic strategies for the treatment of neuropsychiatric disorders. Many of the medications that are used clinically to treat neuropsychiatric disorders have a pharmacological profile that includes being an antagonist at D2-like (D2, D3 and D4) dopamine receptor subtypes. However, dopamine receptor subtypes are involved in a variety of neuronal circuits that include movement coordination, cognition, emotion, affect, memory and the regulation of prolactin. Consequently, antagonism at D2-like receptors can also contribute to some of the adverse side effects associated with the long-term use of antipsychotics including the a) adverse extrapyramidal symptoms associated with the use of typical antipsychotics and b) metabolic side effects (weight gain, hyperglycemia, increased risk of diabetes mellitus, dyslipidemia and gynecomastia) associated with atypical antipsychotic use. Preclinical studies suggest that D3 versus D2 dopamine receptor selective compounds might represent an alternative strategy for the treatment of the symptoms of schizophrenia. In this review we discuss a) how bitropic Nphenylpiperazine D3 dopamine receptor selective compounds have been developed by modification of the primary (orthosteric) and secondary (allosteric or modulatory) pharmacophores to optimize D3 receptor affinity and D2/D3 binding selectivity ratios and b) the functional selectivity of these compounds. Examples of how these compounds might be modified to develop bivalent ligands capable of interacting with receptor dimers or oligomers are also provided. Preclinical studies using bitropic D3 dopamine receptor selective ligands are also discussed as strategy to pharmacologically dissect the role of the D2 and D3 dopamine receptor subtypes in animal models of neuropsychiatric, neurological and substance abuse disorders. This research has the potential to a) advance the understanding of the role of the D2 and D3 dopamine receptor subtypes in neuropsychiatric disorders and b) lead to new treatment strategies for neuropsychiatric disorders.

PMID: 26205291 [PubMed - indexed for MEDLINE]

Allostery: An Overview of Its History, Concepts, Methods, and Applications.

Fri, 06/03/2016 - 06:36

Allostery: An Overview of Its History, Concepts, Methods, and Applications.

PLoS Comput Biol. 2016 Jun;12(6):e1004966

Authors: Liu J, Nussinov R

Abstract
The concept of allostery has evolved in the past century. In this Editorial, we briefly overview the history of allostery, from the pre-allostery nomenclature era starting with the Bohr effect (1904) to the birth of allostery by Monod and Jacob (1961). We describe the evolution of the allostery concept, from a conformational change in a two-state model (1965, 1966) to dynamic allostery in the ensemble model (1999); from multi-subunit (1965) proteins to all proteins (2004). We highlight the current available methods to study allostery and their applications in studies of conformational mechanisms, disease, and allosteric drug discovery. We outline the challenges and future directions that we foresee. Altogether, this Editorial narrates the history of this fundamental concept in the life sciences, its significance, methodologies to detect and predict it, and its application in a broad range of living systems.

PMID: 27253437 [PubMed - as supplied by publisher]

Towards the development of a screening tool to enhance the detection of elder abuse and neglect by emergency medical technicians (EMTs): a qualitative study.

Fri, 06/03/2016 - 06:36

Towards the development of a screening tool to enhance the detection of elder abuse and neglect by emergency medical technicians (EMTs): a qualitative study.

BMC Emerg Med. 2016;16(1):19

Authors: Cannell MB, Jetelina KK, Zavadsky M, Gonzalez JM

Abstract
BACKGROUND: To develop a screening tool to enhance elder abuse and neglect detection and reporting rates among emergency medical technicians (EMTs). Our primary aim was to identify the most salient indicators of elder abuse and neglect for potential inclusion on a screening tool. We also sought to identify practical elements of the tool that would optimize EMT uptake and use in the field, such as format, length and number of items, and types of response options available.
METHODS: Qualitative data were collected from 23 EMTs and Adult Protective Services (APS) caseworkers that participated in one of five semi-structured focus groups. Focus group data were iteratively coded by two coders using inductive thematic identification and data reduction. Findings were subject to interpretation by the research team.
RESULTS: EMTs and APS caseworks identified eight domains of items that might be included on a screening tool: (1) exterior home condition; (2) interior living conditions; (3) social support; (4) medical history; (5) caregiving quality; (6) physical condition of the older adult; (7) older adult's behavior; and, (8) EMTs instincts. The screening tool should be based on observable cues in the physical or social environment, be very brief, easily integrated into electronic charting systems, and provide a decision rule for reporting guidance to optimize utility for EMTs in the field.
CONCLUSIONS: We described characteristics of a screening tool for EMTs to enhance detection and reporting of elder abuse and neglect to APS. Future research should narrow identified items and evaluate how these domains positively predict confirmed cases of elder abuse and neglect.

PMID: 27250247 [PubMed - in process]

Curcumin Mimics the Neurocognitive and Anti-Inflammatory Effects of Caloric Restriction in a Mouse Model of Midlife Obesity.

Fri, 06/03/2016 - 06:36
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Curcumin Mimics the Neurocognitive and Anti-Inflammatory Effects of Caloric Restriction in a Mouse Model of Midlife Obesity.

PLoS One. 2015;10(10):e0140431

Authors: Sarker MR, Franks S, Sumien N, Thangthaeng N, Filipetto F, Forster M

Abstract
Dietary curcumin was studied for its potential to decrease adiposity and reverse obesity- associated cognitive impairment in a mouse model of midlife sedentary obesity. We hypothesized that curcumin intake, by decreasing adiposity, would improve cognitive function in a manner comparable to caloric restriction (CR), a weight loss regimen. 15-month-old male C57BL/6 mice were assigned in groups to receive the following dietary regimens for 12 weeks: (i) a base diet (Ain93M) fed ad libitum (AL), (ii) the base diet restricted to 70% of ad libitum (CR) or (iii) the base diet containing curcumin fed AL (1000 mg/kg diet, CURAL). Blood markers of inflammation, interleukin 6 (IL-6) and C-reactive protein (CRP), as well as an indicator of redox stress (GSH: GSSG ratio), were determined at different time points during the treatments, and visceral and subcutaneous adipose tissue were measured upon completion of the experiment. After 8 weeks of dietary treatment, the mice were tested for spatial cognition (Morris water maze) and cognitive flexibility (discriminated active avoidance). The CR group showed significant weight loss and reduced adiposity, whereas CURAL mice had stable weight throughout the experiment, consumed more food than the AL group, with no reduction of adiposity. However, both CR and CURAL groups took fewer trials than AL to reach criterion during the reversal sessions of the active avoidance task, suggesting an improvement in cognitive flexibility. The AL mice had higher levels of CRP compared to CURAL and CR, and GSH as well as the GSH: GSSG ratio were increased during curcumin intake, suggesting a reducing shift in the redox state. The results suggest that, independent of their effects on adiposity; dietary curcumin and caloric restriction have positive effects on frontal cortical functions that could be linked to anti-inflammatory or antioxidant actions.

PMID: 26473740 [PubMed - indexed for MEDLINE]

Interactive effects of hypoxia, hypercapnia and lung volume on sympathetic nerve activity in humans.

Fri, 06/03/2016 - 06:36
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Interactive effects of hypoxia, hypercapnia and lung volume on sympathetic nerve activity in humans.

Exp Physiol. 2015 Sep;100(9):1018-29

Authors: Jouett NP, Watenpaugh DE, Dunlap ME, Smith ML

Abstract
NEW FINDINGS: What is the central question of this study? The central question of this study was to investigate the interaction of mild exposures to O2 and CO2 on chemoreflex control of SNA and the modulation of lung volume and respiratory phase on this interaction. What is the main finding and its importance? We demonstrate that the synergistic interaction of oxygen- and carbon dioxide-chemosensitive control of the sympathetic nervous system with hypoxia and hypercapnia exists at very mild excitatory stimuli, is significantly overridden by lung inflation and does not extend to inhibitory modulation by hypocapnia in healthy subjects. These findings demonstrate the important inhibitory modulation of sympathetic nerve activity by lung inflation mechanisms in healthy individuals even in the presence of strong sympathoexcitatory stimuli. We hypothesized that simultaneous stimulation of O2 - and CO2 -sensitive chemoreflexes produces synergistic activation of the sympathetic nervous system and that this effect would be most apparent at low lung volume (expiratory) phases of respiration. Each subject (n = 11) breathed 16 gas mixtures in random order: a 4 × 4 matrix of normoxic to hypoxic (8, 12, 16 and 21% O2 ) combined with normocapnic to hypercapnic gases (0, 2, 4 and 6% CO2). Tidal volume, arterial pressure, heart rate and muscle sympathetic nerve activity (MSNA) were measured continuously before and while breathing each gas mixture for 2 min. Changes in MSNA were determined for each gas mixture. The MSNA was subdivided into low and high lung volume and respiratory phases to investigate further modulation by components of normal respiratory phase. Both hypoxia and hypercapnia increased mean MSNA independently. Mean and low lung volume MSNA increased exponentially with increasing levels of combined hypoxia and hypercapnia and resulted in a significant interaction (P < 0.01). In contrast, MSNA during the high lung volume phase of respiration never increased significantly (P > 0.4). Similar but less pronounced effects were found for expiratory and inspiratory phases of respiration. These effects created marked respiratory periodicity in MSNA at higher levels of combined hypoxia and hypercapnia. Finally, the response to hypoxia was not affected by hypocapnia, suggesting that the interaction occurs only during excitatory chemosensitive stimuli. These data indicate that hypoxia and hypercapnia interact to elicit synergistic sympathoexcitation and that withdrawal of sympathoinhibitory effects of lung inflation exaggerates this chemoreflex interaction.

PMID: 26132990 [PubMed - indexed for MEDLINE]

DNA methylation and breast tumor clinicopathological features: the Western New York Exposures and Breast Cancer (WEB) Study.

Thu, 06/02/2016 - 06:47

DNA methylation and breast tumor clinicopathological features: the Western New York Exposures and Breast Cancer (WEB) Study.

Epigenetics. 2016 May 31;:0

Authors: Callahan CL, Wang Y, Marian C, Weng DY, Eng KH, Tao MH, Ambrosone CB, Nie J, Trevisan M, Smiraglia D, Edge SB, Shields PG, Freudenheim JL

Abstract
We evaluated the association between methylation of nine genes, SCGB3A1, GSTP1, RARB, SYK, FHIT, CDKN2A, CCND2, BRCA1, and SFN in tumor samples from 720 breast cancer cases with clinicopathological features of the tumors and survival. Logistic regression was used to estimate odds ratios (OR) of methylation and Cox proportional hazards models to estimate hazard ratios (HR) between methylation and breast cancer related mortality. Estrogen receptor (ER) and progesterone receptor (PR) positivity were associated with increased SCGB3A1 methylation among pre- and post-menopausal cases. Among premenopausal women,compared with Stage 0 cases, cases of invasive cancer were more likely to have increased methylation of RARB (Stage I OR = 4.7, 95% CI: 1.1-19.0; Stage IIA/IIB OR = 9.7, 95% CI: 2.4-39.9; Stage III/IV OR = 5.6, 95% CI: 1.1-29.4) and lower methylation of FHIT (Stage I OR = 0.2, 95% CI: 0.1-0.9; Stage IIA/IIB OR = 0.2, 95% CI: 0.1-0.8; Stage III/IV OR = 0.6, 95% CI: 0.1-3.4). Among postmenopausal women, methylation of SYK was associated with increased tumor size (OR = 1.7, 95% CI: 1.0-2.7) and higher nuclear grade (OR = 2.0, 95% CI 1.2-3.6). Associations between methylation and breast cancer related mortality were observed among pre- but not post-menopausal women. Methylation of SCGB3A1 was associated with reduced risk of death from breast cancer (HR = 0.41, 95% CI: 0.17-0.99) as was BRCA1 (HR = 0.41, 95% CI: 0.16-0.97). CCND2 methylation was associated with increased risk of breast cancer mortality (HR = 3.4, 95% CI: 1.1-10.5). We observed differences in methylation associated with tumor characteristics; methylation of these genes was also associated with breast cancer survival among premenopausal cases. Understanding of the associations of DNA methylation with other clinicopathological features may have implications for prevention and treatment.

PMID: 27245195 [PubMed - as supplied by publisher]

Prognostic value of pretherapy platelet elevation in oropharyngeal cancer patients treated with chemoradiation.

Thu, 06/02/2016 - 06:47
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Prognostic value of pretherapy platelet elevation in oropharyngeal cancer patients treated with chemoradiation.

Int J Cancer. 2016 Mar 1;138(5):1290-7

Authors: Shoultz-Henley S, Garden AS, Mohamed AS, Sheu T, Kroll MH, Rosenthal DI, Gunn GB, Hayes AJ, French C, Eichelberger H, Kalpathy-Cramer J, Smith BD, Phan J, Ayoub Z, Lai SY, Pham B, Kies M, Gold KA, Sturgis E, Fuller CD

Abstract
The purpose of this study is to evaluate potential associations between increased platelets and oncologic outcomes in oropharyngeal cancer patients receiving concurrent chemoradiation. A total of 433 oropharyngeal cancer patients (OPC) treated with intensity-modulated radiation therapy (IMRT) with concurrent chemotherapy between 2002 and 2012 were included under an approved IRB protocol. Complete blood count (CBC) data were extracted. Platelet and hemoglobin from the last phlebotomy (PLTpre-chemoRT, Hgbpre-chemoRT ) before start of treatment were identified. Patients were risk-stratified using Dahlstrom-Sturgis criteria and were tested for association with survival and disease-control outcomes. Locoregional control (LRC), freedom from distant metastasis (FDM) and overall survival (OS) were decreased (p < 0.03, p < 0.04 and p < 0.0001, respectively) for patients with PLTpre-chemoRT value of ≥350 × 10(9) /L. Actuarial 5-year locoregional control (LRC) and FDM were 83 and 85% for non-thrombocythemic patients while patient with high platelets had 5-year LRC and FDM of 73 and 74%, respectively. Likewise, 5-year OS was better for patients with normal platelet counts by comparison (76 vs. 57%; p < 0.0001). Comparison of univariate parametric models demonstrated that PLTpre-chemoRT was better among tested models. Multivariate assessment demonstrated improved performance of models which included pretherapy platelet indices. On Bayesian information criteria analysis, the optimal prognostic model was then used to develop nomograms predicting 3-, 5- and 10-year OS. In conclusion, pretreatment platelet elevation is a promising predictor of prognosis, and further work should be done to elucidate the utility of antiplatelets in modifying risk in OPC patients.

PMID: 26414107 [PubMed - indexed for MEDLINE]

Genetic analysis of the Yavapai Native Americans from West-Central Arizona using the Illumina MiSeq FGx™ forensic genomics system.

Wed, 06/01/2016 - 06:30

Genetic analysis of the Yavapai Native Americans from West-Central Arizona using the Illumina MiSeq FGx™ forensic genomics system.

Forensic Sci Int Genet. 2016 May 17;24:18-23

Authors: Wendt FR, Churchill JD, Novroski NM, King JL, Ng J, Oldt RF, McCulloh KL, Weise JA, Smith DG, Kanthaswamy S, Budowle B

Abstract
Forensically-relevant genetic markers were typed for sixty-two Yavapai Native Americans using the ForenSeq™ DNA Signature Prep Kit.These data are invaluable to the human identity community due to the greater genetic differentiation among Native American tribes than among other subdivisions within major populations of the United States. Autosomal, X-chromosomal, and Y-chromosomal short tandem repeat (STR) and identity-informative (iSNPs), ancestry-informative (aSNPs), and phenotype-informative (pSNPs) single nucleotide polymorphism (SNP) allele frequencies are reported. Sequence-based allelic variants were observed in 13 autosomal, 3 X, and 3 Y STRs. These observations increased observed and expected heterozygosities for autosomal STRs by 0.081±0.068 and 0.073±0.063, respectively, and decreased single-locus random match probabilities by 0.051±0.043 for 13 autosomal STRs. The autosomal random match probabilities (RMPs) were 2.37×10-26 and 2.81×10-29 for length-based and sequence-based alleles, respectively. There were 22 and 25 unique Y-STR haplotypes among 26 males, generating haplotype diversities of 0.95 and 0.96, for length-based and sequencebased alleles, respectively. Of the 26 haplotypes generated, 17 were assigned to haplogroup Q, three to haplogroup R1b, two each to haplogroups E1b1b and L, and one each to haplogroups R1a and I1. Male and female sequence-based X-STR random match probabilities were 3.28×10-7 and 1.22×10-6, respectively. The average observed and expected heterozygosities for 94 iSNPs were 0.39±0.12 and 0.39±0.13, respectively, and the combined iSNP RMP was 1.08×10-32. The combined STR and iSNP RMPs were 2.55×10-58 and 3.02×10-61 for length-based and sequence-based STR alleles, respectively. Ancestry and phenotypic SNP information, performed using the ForenSeq™ Universal Analysis Software, predicted black hair, brown eyes, and some probability of East Asian ancestry for all but one sample that clustered between European and Admixed American ancestry on a principal components analysis. These data serve as the first population assessment using the ForenSeq™ panel and highlight the value of employing sequence-based alleles for forensic DNA typing to increase heterozygosity, which is beneficial for identity testing in populations with reduced genetic diversity.

PMID: 27243782 [PubMed - as supplied by publisher]

Prevalence and Predictors of Hypertension in the Labor Force Population in China: Results from a Cross-sectional Survey in Xinjiang Uygur Autonomous Region.

Wed, 06/01/2016 - 06:30

Prevalence and Predictors of Hypertension in the Labor Force Population in China: Results from a Cross-sectional Survey in Xinjiang Uygur Autonomous Region.

Biomed Environ Sci. 2016 Apr;29(4):290-4

Authors: Xu de M, Li XF, Goan D, Yang de M, Li JM, Wang X, Huang YL, Chen YS

Abstract
The objective of this study was to examine the prevalence of hypertension and identify its contributory factors in the labor force population in Karamay. A total of 2819 adults (55.9% male adults) were interviewed and examined. The overall crude prevalence of hypertension was 32.4%. Among 914 hypertensive patients, 34.8% were aware of their diagnosis, 22.1% received treatment, and 5.6% achieved blood pressure control. Hypertension was significantly correlated with age, overweight/obesity, central obesity, diabetes, and dyslipidemia in both men and women. In addition, less education, alcohol consumption, and less walking were risk factors for men. Effective hypertension prevention and control programs are urgently needed to decrease the burden of hypertension in this region.

PMID: 27241740 [PubMed - in process]

A Three-Way Interaction among Maternal and Fetal Variants Contributing to Congenital Heart Defects.

Wed, 06/01/2016 - 06:30
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A Three-Way Interaction among Maternal and Fetal Variants Contributing to Congenital Heart Defects.

Ann Hum Genet. 2016 Jan;80(1):20-31

Authors: Li M, Li J, Wei C, Lu Q, Tang X, Erickson SW, MacLeod SL, Hobbs CA

Abstract
Congenital heart defects (CHDs) develop through a complex interplay between genetic variants, epigenetic modifications, and maternal environmental exposures. Genetic studies of CHDs have commonly tested single genetic variants for association with CHDs. Less attention has been given to complex gene-by-gene and gene-by-environment interactions. In this study, we applied a recently developed likelihood-ratio Mann-Whitney (LRMW) method to detect joint actions among maternal variants, fetal variants, and maternal environmental exposures, allowing for high-order statistical interactions. All subjects are participants from the National Birth Defect Prevention Study, including 623 mother-offspring pairs with CHD-affected pregnancies and 875 mother-offspring pairs with unaffected pregnancies. Each individual has 872 single nucleotide polymorphisms encoding for critical enzymes in the homocysteine, folate, and trans-sulfuration pathways. By using the LRMW method, three variants (fetal rs625879, maternal rs2169650, and maternal rs8177441) were identified with a joint association to CHD risk (nominal P-value = 1.13e-07). These three variants are located within genes BHMT2, GSTP1, and GPX3, respectively. Further examination indicated that maternal SNP rs2169650 may interact with both fetal SNP rs625879 and maternal SNP rs8177441. Our findings suggest that the risk of CHD may be influenced by both the intragenerational interaction within the maternal genome and the intergenerational interaction between maternal and fetal genomes.

PMID: 26612412 [PubMed - indexed for MEDLINE]

Store-operated calcium entry and diabetic complications.

Wed, 06/01/2016 - 06:30
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Store-operated calcium entry and diabetic complications.

Exp Biol Med (Maywood). 2016 Feb;241(4):343-52

Authors: Chaudhari S, Ma R

Abstract
Store-operated Ca(2+) entry (SOCE) is mediated by the store-operated Ca(2+) channel (SOC) that opens upon depletion of internal Ca(2+) stores following activation of G protein-coupled receptors or receptor tyrosine kinases. Over the past two decades, the physiological and pathological relevance of SOCE has been extensively studied. Recently, accumulating evidence suggests associations of altered SOCE with diabetic complications. This review focuses on the implication of SOCE as it pertains to various complications resulting from diabetes. We summarize recent findings by us and others on the involvement of abnormal SOCE in the development of diabetic complications, such as diabetic nephropathy and diabetic vasculopathy. The underlying mechanisms that mediate the diabetes-associated alterations of SOCE are also discussed. The SOCE pathway may be considered as a potential therapeutic target for diabetes-associated diseases.

PMID: 26468167 [PubMed - indexed for MEDLINE]

Lipoprotein-associated phospholipase A2, homocysteine, and Alzheimer's disease.

Tue, 05/31/2016 - 06:31

Lipoprotein-associated phospholipase A2, homocysteine, and Alzheimer's disease.

Alzheimers Dement (Amst). 2015 Dec;1(4):464-71

Authors: Doody RS, Demirovic J, Ballantyne CM, Chan W, Barber R, Powell S, Pavlik V, Texas Alzheimer's Disease Research and Care Consortium

Abstract
INTRODUCTION: Lipoprotein-associated phospholipase A2 (Lp-PLA2) and homocysteine (Hcy) have been linked to inflammation and Alzheimer's disease (AD). Using a case-control design, we examined their independent effects and interactions with cardiovascular disease equivalent (CVDE), on AD risk.
METHODS: AD cases and controls were from the Texas Alzheimer's Research and Care Consortium study. Lp-PLA2 was determined using the PLAC test (diaDexus, Inc), and Hcy by recombinant cycling assay (Roche Hitachi 911). Logistic regression was used to predict AD case status. We assayed for Lp-PLA2 in the brain tissue of cases and controls.
RESULTS: AD case status was independently associated with Lp-PLA2 and Hcy above the median (odds ratio [OR] = 1.91; 95% confidence interval [CI] = 1.22-2.97; P < .001 and OR = 1.81; 95% CI = 1.16-2.82; P = .009, respectively). Lp-PLA2, but not Hcy, interacted with CVDE to increase risk. Lp-PLA2 was absent from the brain tissue in both groups.
DISCUSSION: Higher Lp-PLA2 and Hcy are independently associated with AD. The association of Lp-PLA2 with AD may be mediated through vascular damage.

PMID: 27239525 [PubMed]

Serum-based protein profiles of Alzheimer's disease and mild cognitive impairment in elderly Hispanics.

Sat, 05/28/2016 - 06:30

Serum-based protein profiles of Alzheimer's disease and mild cognitive impairment in elderly Hispanics.

Neurodegener Dis Manag. 2016 May 27;

Authors: Villarreal AE, O'Bryant SE, Edwards M, Grajales S, Britton GB, Panama Aging Research Initiative

Abstract
AIM: To describe the biomarker profiles in elderly Panamanians diagnosed with Alzheimer's disease (AD), mild cognitive impairment (MCI) or no impairment using serum-based biomarkers.
METHODS: Twenty-four proteins were analyzed using an electrochemiluminescence-based multiplex biomarker assay platform. A biomarker profile was generated using random forest analyses.
RESULTS: Two proteins differed among groups: IL-18 and T-lymphocyte-secreted protein I-309. The AD profile was highly accurate and independent of age, gender, education and Apolipoprotein E ε4 status. AD and MCI profiles had substantial overlap among the top markers, suggesting common functions in AD and MCI but differences in their relative importance.
CONCLUSION: Our results underscore the potential influence of genetic and environmental differences within Hispanic populations on the proteomic profile of AD.

PMID: 27229914 [PubMed - as supplied by publisher]

Perforators, the Underlying Anatomy of Acupuncture Points.

Fri, 05/27/2016 - 06:30
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Perforators, the Underlying Anatomy of Acupuncture Points.

Altern Ther Health Med. 2016 Mar;22(3):25-30

Authors: Zhi Wei D, Yu S, Yongqiang Z

Abstract
Context • As a critical concept in acupuncture, acupuncture points, or acupoints for short, are currently believed to be 3-dimensional structures composed of skin, muscles, tendons, nerves, blood vessels, lymph nodes, and other special tissues. No known specific tissue or organ has been confirmed to be an acupoint. However, from a microsurgeon's point of view, a special vascular structure exists around each acupoint (ie, perforators or arterioles of 0.3-1.5 mm that pierce deeply through the fascia). Objective • The current research team investigated the theory that perforators are the anatomical basis of acupoints. Design • A reference list of acupoints and of perforators near the acupoints was proposed, and the distributions were analyzed. Using the World Health Organization (WHO) list, "Standard Acupuncture Point Locations in the Western Pacific Region," 2 experienced acupuncturists identified the needling depth and angle as well as verified the acupoint locations. Perforators with amplitudes of 1 cm or more were identified by 3 veteran microsurgeons. Setting • The study was carried out in an osteopathic research center at the 89th Hospital of the People's Liberation Army, in Weifang, Shandong, China. From October 2013 to October 2014, patients who required skin flap transplantation were enrolled for observation. Outcome Measures • To evaluate the theory, the current research team observed subcutaneous perforating points in flap donor sites and operative incision areas and compared those points with the acupoints located by acupuncturists. Results • The perforators and acupoints were found to be closely correlated. Several distribution patterns of acupoints and perforators have emerged and further confirmed the research team's theory. Conclusions • The hypothesis could facilitate theoretical understanding of the mechanism and essence of acupuncture.

PMID: 27228269 [PubMed - as supplied by publisher]

Caspase-3-Dependent Proteolytic Cleavage of Tau Causes Neurofibrillary Tangles and Results in Cognitive Impairment During Normal Aging.

Thu, 05/26/2016 - 06:29

Caspase-3-Dependent Proteolytic Cleavage of Tau Causes Neurofibrillary Tangles and Results in Cognitive Impairment During Normal Aging.

Neurochem Res. 2016 May 25;

Authors: Means JC, Gerdes BC, Kaja S, Sumien N, Payne AJ, Stark DA, Borden PK, Price JL, Koulen P

Abstract
Mouse models of neurodegenerative diseases such as Alzheimer's disease (AD) are important for understanding how pathological signaling cascades change neural circuitry and with time interrupt cognitive function. Here, we introduce a non-genetic preclinical model for aging and show that it exhibits cleaved tau protein, active caspases and neurofibrillary tangles, hallmarks of AD, causing behavioral deficits measuring cognitive impairment. To our knowledge this is the first report of a non-transgenic, non-interventional mouse model displaying structural, functional and molecular aging deficits associated with AD and other tauopathies in humans with potentially high impact on both new basic research into pathogenic mechanisms and new translational research efforts. Tau aggregation is a hallmark of tauopathies, including AD. Recent studies have indicated that cleavage of tau plays an important role in both tau aggregation and disease. In this study we use wild type mice as a model for normal aging and resulting age-related cognitive impairment. We provide evidence that aged mice have increased levels of activated caspases, which significantly correlates with increased levels of truncated tau and formation of neurofibrillary tangles. In addition, cognitive decline was significantly correlated with increased levels of caspase activity and tau truncated by caspase-3. Experimentally induced inhibition of caspases prevented this proteolytic cleavage of tau and the associated formation of neurofibrillary tangles. Our study shows the strength of using a non-transgenic model to study structure, function and molecular mechanisms in aging and age related diseases of the brain.

PMID: 27220334 [PubMed - as supplied by publisher]

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]

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