Recent Research Articles from UNTHSC

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Dexamethasone induces a putative repressor complex and chromatin modifications in the CRH promoter.

Fri, 04/18/2014 - 2:15pm
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Dexamethasone induces a putative repressor complex and chromatin modifications in the CRH promoter.

Mol Endocrinol. 2013 Jul;27(7):1142-52

Authors: Sharma D, Bhave S, Gregg E, Uht R

Abstract
Glucocorticoids down-regulate expression of hypothalamic CRH; however, mechanisms by which they do so are not fully understood. The proximal promoter cAMP response element, negative glucocorticoid response element (nGRE), and methylated CpG islands all play a role in crh down-regulation. Dexamethasone (Dex)-repressed crh expression is associated with glucocorticoid receptor (GR) and histone deacetylase 1 (HDAC1) recruitment to the region of the crh promoter. Given that HDAC1 may be present in methylated CpG binding protein 2 (MeCP2) complexes, and that MeCP2 is known to play a role in regulating crh expression, we sought to determine whether or not HDAC1 and/or MeCP2 could interact with the GR. Dex enhanced GR interactions with both proteins. Glucocorticoid regulation of crh has also been associated with CpG methylation; thus we assessed whether GR could interact with a DNA methyltransferase (DnMT). Indeed, the GR interacted with DnMT3b, but not DnMT3a. In addition, Dex-induced occupancy of the crh promoter by HDAC1, MeCP2, and DnMT3b was associated with an increased level of promoter methylation, which appeared to be CpG site specific. Lastly, to extend previous assessment of chromatin modifications in this promoter region, the degree of histone methylation was measured. Dex increased trimethylation of histone 3-lysine 9, a marker of gene suppression; however, levels of di- and trimethylated histone 3-lysine 4, markers of gene activation, were not significantly changed. Taken together, the data suggest that Dex-mediated crh suppression involves formation of a repressor complex consisting of GR, MeCP2, and HDAC1, recruitment of DnMT3b, and associated changes in proximal promoter CpG methylation.

PMID: 23671328 [PubMed - indexed for MEDLINE]

The Link between Sleep Disturbance and Depression among Mexican Americans: A Project FRONTIER Study.

Fri, 04/18/2014 - 4:55am

The Link between Sleep Disturbance and Depression among Mexican Americans: A Project FRONTIER Study.

J Clin Sleep Med. 2014;10(4):427-31

Authors: Roane BM, Johnson L, Edwards M, Hall J, Al-Farra S, O'Bryant SE

Abstract
OBJECTIVE: To examine the link between disturbed sleep and depression scores in Mexican Americans and non-Hispanic Whites.
METHODS: Data were analyzed for 566 participants (45% Mexican Americans) who were part of a rural healthcare study, Project FRONTIER. Mean age was 55.5 years for Mexican Americans (70% female) and 65.6 years for non-Hispanic Whites (69% female). Self-reported sleep disturbance was entered as the predictor, GDS-30 total and factor scores as the outcome variables, and age, sex, education, BMI, and medical diagnoses (hyperlipidemia, diabetes mellitus, and hypertension) entered as covariates.
RESULTS: Mexican Americans reported higher rates of sleep disturbances (25%) than non-Hispanic whites (17%). Sleep disturbances were significantly associated with GDS-30 total scores and the factors Dysphoria and Cognitive Impairment in both Mexican Americans and non-Hispanic whites.
CONCLUSIONS: In this study, Mexican Americans reported higher rates of sleep disturbances than non-Hispanic whites. Disturbed sleep was positively associated with depression and the factor scores for Dysphoria and Cognitive Impairment in both groups. Given the paucity of research on sleep disorders in Mexican Americans, identifying what sleep disorders are present and the impact treating these sleep disorders have on depression warrant further investigation.
CITATION: Roane BM; Johnson L; Edwards M; Hall J; Al-Farra S; O'Bryant SE. The link between sleep disturbance and depression among Mexican Americans: a Project FRONTIER study. J Clin Sleep Med 2014;10(4):427-431.

PMID: 24733989 [PubMed - in process]

Evidence of brain tumor stem progenitor-like cells with low proliferative capacity in human benign pituitary adenoma.

Fri, 04/18/2014 - 4:55am

Evidence of brain tumor stem progenitor-like cells with low proliferative capacity in human benign pituitary adenoma.

Cancer Lett. 2014 Apr 11;

Authors: Chen L, Ye H, Wang X, Tang X, Mao Y, Zhao Y, Wu Z, Mao XO, Xie L, Jin K, Yao Y

Abstract
Tumor stem cells have been implicated as cancer-initiating cells in malignant brain tumors. However, whether benign brain tumors also contain tumor stem cells are largely unexplored. Here, we investigated whether tumor stem-like cells were present in pituitary adenoma similar to malignant brain tumors. By immunocytochemistry, we found that pituitary adenoma tissues expressed neural stem cell marker. These cells could form neurospheres in vitro, expressed neural stem/progenitor cell markers and generated daughter cells with the capacity to differentiate into three neural lineages. Importantly, compared with non-invasive pituitary adenomas, we found that CD133 expression was significantly increased in invasive pituitary adenomas, suggesting that the proliferative capacity was correlated with the malignance of pituitary adenomas. Finally, invasive pituitary adenomas cells displayed lower proliferative ability than glioblastoma. Our data indicate that a subpopulation of stem/progenitor-like cells are present in pituitary adenomas, and these cells may be responsible for benign tumor initiation and maintenance.

PMID: 24732807 [PubMed - as supplied by publisher]

The effect of SV 293, a D2 dopamine receptor-selective antagonist, on D2 receptor-mediated GIRK channel activation and adenylyl cyclase inhibition.

Fri, 04/18/2014 - 4:55am
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The effect of SV 293, a D2 dopamine receptor-selective antagonist, on D2 receptor-mediated GIRK channel activation and adenylyl cyclase inhibition.

Pharmacology. 2013;92(1-2):84-9

Authors: Huang R, Griffin SA, Taylor M, Vangveravong S, Mach RH, Dillon GH, Luedtke RR

Abstract
SV 293 [1-([5-methoxy-1H-indol-3-yl]methyl)-4-(4-[methylthio]​phenyl)piperidin-4-ol] binds with 100-fold higher affinity to human D2 receptors compared to the human D3 and D4 dopamine receptor subtypes. We investigated the intrinsic efficacy of this compound at the D2 dopamine receptor subtype using both: (1) a forskolin-dependent adenylyl cyclase inhibition assay and (2) an electrophysiological assay for evaluating coupling to G-protein-coupled inwardly rectifying potassium channels. In both assays SV 293 was found to be a neutral antagonist capable of blocking the effects of the full D2-like receptor agonist quinpirole. Based upon these results we propose that SV 293 is a useful pharmacological tool that can be used for both in vitro and in vivo studies to investigate the role of D2-like dopamine receptor subtypes in neurological, neuropsychiatric and movement disorders where dopaminergic pathways have been implicated.

PMID: 23942137 [PubMed - indexed for MEDLINE]

Interleukin-23 (IL-23) deficiency disrupts Th17 and Th1-related defenses against Streptococcus pneumoniae infection.

Fri, 04/18/2014 - 4:55am
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Interleukin-23 (IL-23) deficiency disrupts Th17 and Th1-related defenses against Streptococcus pneumoniae infection.

Cytokine. 2013 Oct;64(1):375-81

Authors: Kim BJ, Lee S, Berg RE, Simecka JW, Jones HP

Abstract
Resolution of acute of infection caused by capsular Streptococcus pneumoniae infection in the absence of effective antibiotic therapy requires tight regulation of immune and inflammatory responses. To provide new mechanistic insight of the requirements needed for innate host defenses against acute S. pneumoniae infection, we examined how IL-23 deficiency mediated acute pulmonary resistance. We found that IL-23 deficient mice were more susceptible to bacterial colonization in the lungs corresponding with greater bacterial dissemination. The lack of IL-23 was found to decrease IL-6 and IL-12p70 cytokine levels in bronchiolar lavage within the initial day after infection. Pulmonary leukocytes isolated from infected IL-23 deficient mice demonstrated a dramatic decrease in IL-17A and IFN-γ in response to heat-killed organisms. These findings corresponded with significant abrogation of neutrophilic infiltrate in the lungs compared to IL-23 competent mice. Whereas previous studies have shown opposing influences of IL-12/IL-23 regulation, our findings suggest a concordant dependency of IL-23 expression on Th1 and Th17-related responses.

PMID: 23752068 [PubMed - indexed for MEDLINE]

The Multifunctional Protein Kinase C-ε in Cancer Development and Progression.

Wed, 04/16/2014 - 4:47am

The Multifunctional Protein Kinase C-ε in Cancer Development and Progression.

Cancers (Basel). 2014;6(2):860-78

Authors: Jain K, Basu A

Abstract
The protein kinase C (PKC) family proteins are important signal transducers and have long been the focus of cancer research. PKCɛ, a member of this family, is overexpressed in most solid tumors and plays critical roles in different processes that lead to cancer development. Studies using cell lines and animal models demonstrated the transforming potential of PKCɛ. While earlier research established the survival functions of PKCɛ, recent studies revealed its role in cell migration, invasion and cancer metastasis. PKCɛ has also been implicated in epithelial to mesenchymal transition (EMT), which may be the underlying mechanism by which it contributes to cell motility. In addition, PKCɛ affects cell-extracellular matrix (ECM) interactions by direct regulation of the cytoskeletal elements. Recent studies have also linked PKCɛ signaling to cancer stem cell functioning. This review focuses on the role of PKCɛ in different processes that lead to cancer development and progression. We also discussed current literatures on the pursuit of PKCɛ as a target for cancer therapy.

PMID: 24727247 [PubMed]

Between-centre variability in transfer function analysis, a widely used method for linear quantification of the dynamic pressure-flow relation: The CARNet study.

Wed, 04/16/2014 - 4:47am

Between-centre variability in transfer function analysis, a widely used method for linear quantification of the dynamic pressure-flow relation: The CARNet study.

Med Eng Phys. 2014 Apr 8;

Authors: Meel-van den Abeelen AS, Simpson DM, Wang LJ, Slump CH, Zhang R, Tarumi T, Rickards CA, Payne S, Mitsis GD, Kostoglou K, Marmarelis V, Shin D, Tzeng YC, Ainslie PN, Gommer E, Müller M, Dorado AC, Smielewski P, Yelicich B, Puppo C, Liu X, Czosnyka M, Wang CY, Novak V, Panerai RB, Claassen JA

Abstract
Transfer function analysis (TFA) is a frequently used method to assess dynamic cerebral autoregulation (CA) using spontaneous oscillations in blood pressure (BP) and cerebral blood flow velocity (CBFV). However, controversies and variations exist in how research groups utilise TFA, causing high variability in interpretation. The objective of this study was to evaluate between-centre variability in TFA outcome metrics. 15 centres analysed the same 70 BP and CBFV datasets from healthy subjects (n=50 rest; n=20 during hypercapnia); 10 additional datasets were computer-generated. Each centre used their in-house TFA methods; however, certain parameters were specified to reduce a priori between-centre variability. Hypercapnia was used to assess discriminatory performance and synthetic data to evaluate effects of parameter settings. Results were analysed using the Mann-Whitney test and logistic regression. A large non-homogeneous variation was found in TFA outcome metrics between the centres. Logistic regression demonstrated that 11 centres were able to distinguish between normal and impaired CA with an AUC>0.85. Further analysis identified TFA settings that are associated with large variation in outcome measures. These results indicate the need for standardisation of TFA settings in order to reduce between-centre variability and to allow accurate comparison between studies. Suggestions on optimal signal processing methods are proposed.

PMID: 24725709 [PubMed - as supplied by publisher]

Proteomic analysis of signaling network regulation in renal cell carcinomas with differential hypoxia-inducible factor-2α expression.

Wed, 04/16/2014 - 4:47am
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Proteomic analysis of signaling network regulation in renal cell carcinomas with differential hypoxia-inducible factor-2α expression.

PLoS One. 2013;8(8):e71654

Authors: Nagaprashantha LD, Talamantes T, Singhal J, Guo J, Vatsyayan R, Rauniyar N, Awasthi S, Singhal SS, Prokai L

Abstract
BACKGROUND: The loss of von Hippel-Lindau (VHL) protein function leads to highly vascular renal tumors characterized by an aggressive course of disease and refractoriness to chemotherapy and radiotherapy. Loss of VHL in renal tumors also differs from tumors of other organs in that the oncogenic cascade is mediated by an increase in the levels of hypoxia-inducible factor-2α (HIF2α) instead of hypoxia-inducible factor-1α (HIF1α).
METHODS AND PRINCIPAL FINDINGS: We used renal carcinoma cell lines that recapitulate the differences between mutant VHL and wild-type VHL genotypes. Utilizing a method relying on extracted peptide intensities as a label-free approach for quantitation by liquid chromatography-mass spectrometry, our proteomics study revealed regulation of key proteins important for cancer cell survival, proliferation and stress-resistance, and implicated differential regulation of signaling networks in VHL-mutant renal cell carcinoma. We also observed upregulation of cellular energy pathway enzymes and the stress-responsive mitochondrial 60-kDa heat shock protein. Finding reliance on glutaminolysis in VHL-mutant renal cell carcinoma was of particular significance, given the generally predominant dependence of tumors on glycolysis. The data have been deposited to the ProteomeXchange with identifier PXD000335.
CONCLUSIONS AND SIGNIFICANCE: Pathway analyses provided corroborative evidence for differential regulation of molecular and cellular functions influencing cancer energetics, metabolism and cell proliferation in renal cell carcinoma with distinct VHL genotype. Collectively, the differentially regulated proteome characterized by this study can potentially guide translational research specifically aimed at effective clinical interventions for advanced VHL-mutant, HIF2α-over-expressing tumors.

PMID: 23940778 [PubMed - indexed for MEDLINE]

Astragaloside IV prevents damage to human mesangial cells through the inhibition of the NADPH oxidase/ROS/Akt/NF‑κB pathway under high glucose conditions.

Tue, 04/15/2014 - 4:22am

Astragaloside IV prevents damage to human mesangial cells through the inhibition of the NADPH oxidase/ROS/Akt/NF‑κB pathway under high glucose conditions.

Int J Mol Med. 2014 Apr 9;

Authors: Sun L, Li W, Li W, Xiong L, Li G, Ma R

Abstract
Glomerular hypertrophy and hyperfiltration are the two major pathological characteristics of the early stages of diabetic nephropathy (DN), which are respectively related to mesangial cell (MC) proliferation and a decrease in calcium influx conducted by canonical transient receptor potential cation channel 6 (TRPC6). The marked increase in the production of reactive oxygen species (ROS) induced by hyperglycemia is the main sponsor of multiple pathological pathways in DN. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is an important source of ROS production in MCs. Astragaloside IV (AS‑IV) is an active ingredient of Radix Astragali which has a potent antioxidative effect. In this study, we aimed to investigate whether high glucose (HG)‑induced NADPH oxidase activation and ROS production contribute to MC proliferation and the downregulation of TRPC6 expression; we also wished to determine the effects of AS‑IV on MCs under HG conditions. Using a human glomerular mesangial cell line, we found that treatment with AS‑IV for 48 h markedly attenuated HG‑induced proliferation and the hypertrophy of MCs in a dose‑dependent manner. The intracellular ROS level was also markedly reduced following treatment with AS‑IV. In addition, the enhanced activity of NADPH oxidase and the expression level of NADPH oxidase 4 (Nox4) protein were decreased. Treatment with AS‑IV also inhibited the phosphorylation level of Akt and IκBα in the MCs. In addition, TRPC6 protein expression and the intracellular free calcium concentration were also markedly reduced following treatment with AS‑IV under HG conditions. These results suggest that AS‑IV inhibits HG‑induced mesangial cell proliferation and glomerular contractile dysfunction through the NADPH oxidase/ROS/Akt/nuclear factor‑κB (NF‑κB) pathway, providing a new perspective for the clinical treatment of DN.

PMID: 24718766 [PubMed - as supplied by publisher]

Neural stem cell protects aged rat brain from ischemia-reperfusion injury through neurogenesis and angiogenesis.

Fri, 04/11/2014 - 3:24am

Neural stem cell protects aged rat brain from ischemia-reperfusion injury through neurogenesis and angiogenesis.

J Cereb Blood Flow Metab. 2014 Apr 9;

Authors: Tang Y, Wang J, Lin X, Wang L, Shao B, Jin K, Wang Y, Yang GY

Abstract
Neural stem cells (NSCs) show therapeutic potential for ischemia in young-adult animals. However, the effect of aging on NSC therapy is largely unknown. In this work, NSCs were transplanted into aged (24-month-old) and young-adult (3-month-old) rats at 1 day after stroke. Infarct volume and neurobehavioral outcomes were examined. The number of differentiated NSCs was compared in aged and young-adult ischemic rats and angiogenesis and neurogenesis were also determined. We found that aged rats developed larger infarcts than young-adult rats after ischemia (P<0.05). The neurobehavioral outcome was also worse for aged rats comparing with young-adult rats. Brain infarction and neurologic deficits were attenuated after NSC transplantation in both aged and young-adult rats. The number of survived NSCs in aged rats was similar to that of the young-adult rats (P>0.05) and most of them were differentiated into glial fibrillary acidic protein(+) (GFAP(+)) cells. More importantly, angiogenesis and neurogenesis were greatly enhanced in both aged and young-adult rats after transplantation compared with phosphate-buffered saline (PBS) control (P<0.05), accompanied by increased expression of vascular endothelial growth factor (VEGF). Our results showed that NSC therapy reduced ischemic brain injury, along with increased angiogenesis and neurogenesis in aged rats, suggesting that aging-related microenvironment does not preclude a beneficial response to NSCs transplantation during cerebral ischemia.Journal of Cerebral Blood Flow & Metabolism advance online publication, 9 April 2014; doi:10.1038/jcbfm.2014.61.

PMID: 24714034 [PubMed - as supplied by publisher]

Diversity of piroplasms detected in blood-fed and questing ticks from several states in the United States.

Thu, 04/10/2014 - 4:39am

Diversity of piroplasms detected in blood-fed and questing ticks from several states in the United States.

Ticks Tick Borne Dis. 2014 Apr 4;

Authors: Shock BC, Moncayo A, Cohen S, Mitchell EA, Williamson PC, Lopez G, Garrison LE, Yabsley MJ

Abstract
Piroplasms in the genera Babesia, Theileria, and Cytauxzoon are tick-borne parasites that may be animal and human pathogens. Most piroplasms with known life cycles are transmitted by ixodid ticks; however, for many species, the vector is unknown. This study was conducted to determine the prevalence and diversity of piroplasms in ticks from several US states. Piroplasm-specific polymerase chain reaction (PCR) assays were used to test 1631 ticks from Georgia (n=486), Kentucky (n=103), Pennsylvania (n=1), Tennessee (n=626), and Texas (n=414). Ticks were either questing (n=42) or collected from animals (n=627) or humans (n=962). The 2 primary species tested were Dermacentor variabilis (n=702) and Amblyomma americanum (n=743), but Amblyomma cajennense (n=99), Amblyomma maculatum (n=16), Ixodes scapularis (n=4), I. woodi (n=1), and unidentified Amblyomma spp. nymphs (n=64) were also tested. A low prevalence of piroplasms was detected with 37 (2.3%), 35 (2.1%), and 9 (0.6%) ticks positive for Theileria spp., Babesia spp., or Cytauxzoon felis, respectively. Based on sequence analysis, at least 6 Babesia spp. were detected and 15 of the 35 (41%) Babesia-positive ticks were A. americanum, 19 (56%) were D. variabilis, and one (3%) was an I. scapularis. Nine Babesia-positive ticks were removed from humans from Kentucky (n=1), Georgia (n=2), Texas (n=5), and Pennsylvania (n=1). Three Babesia-positive ticks were questing A. americanum which represents the first report of Babesia-infected questing Amblyomma in the US. Theileria infections were only detected in A. americanum, and all sequences were similar to white-tailed deer associated Theileria spp. C. felis was only detected in D. variabilis. These data suggest that A. americanum may be a vector of Babesia spp., although experimental studies are needed to confirm vector competence. Finally, these data demonstrate a high diversity of piroplasms in both questing and partially fed ticks in the US; although, host-blood meals can be present in non-questing ticks.

PMID: 24709338 [PubMed - as supplied by publisher]

Internal Validation of Human Mitochondrial DNA Quantification Using Real-Time PCR.

Thu, 04/10/2014 - 4:39am

Internal Validation of Human Mitochondrial DNA Quantification Using Real-Time PCR.

J Forensic Sci. 2014 Apr 7;

Authors: Sprouse ML, Phillips NR, Kavlick MF, Roby RK

Abstract
The quantity of mitochondrial DNA (mtDNA) template added for amplification and subsequent dye terminator reactions is critical for obtaining quality sequence data. Validation of a human mtDNA real-time quantitative PCR (qPCR) assay demonstrated its high degree of reproducibility and precision as well as an extremely sensitive threshold of detection (0.0001 pg/μL or approximately six human mtDNA copies/μL). A study of 35 nonprobative bone and teeth evidence samples revealed that 20 pg of mtDNA template is recommended for successful HV1 and HV2 sequence analysis; however, as little as 0.013 pg can generate a full mtDNA profile when using enhanced amplification reactions. The assay can also detect PCR inhibition and is useful for identifying samples that may benefit from re-purification. Overall, the assay is an excellent method to quantify mtDNA and is useful for determining the best analytical approach for successful sequencing.

PMID: 24708529 [PubMed - as supplied by publisher]

Erratum to: Modeling one complete versus triplicate analyses in low template DNA typing.

Wed, 04/09/2014 - 4:24am

Erratum to: Modeling one complete versus triplicate analyses in low template DNA typing.

Int J Legal Med. 2014 Apr 6;

Authors: Ge J, Budowle B

PMID: 24705733 [PubMed - as supplied by publisher]

Changes in biomechanical dysfunction and low back pain reduction with osteopathic manual treatment: Results from the OSTEOPATHIC Trial.

Wed, 04/09/2014 - 4:24am

Changes in biomechanical dysfunction and low back pain reduction with osteopathic manual treatment: Results from the OSTEOPATHIC Trial.

Man Ther. 2014 Mar 18;

Authors: Licciardone JC, Kearns CM, Crow WT

Abstract
The purpose of this study was to measure changes in biomechanical dysfunction following osteopathic manual treatment (OMT) and to assess how such changes predict subsequent low back pain (LBP) outcomes. Secondary analyses were performed with data collected during the OSTEOPATHIC Trial wherein a randomized, double-blind, sham-controlled, 2 × 2 factorial design was used to study OMT for chronic LBP. At baseline, prevalence rates of non-neutral lumbar dysfunction, pubic shear, innominate shear, restricted sacral nutation, and psoas syndrome were determined in 230 patients who received OMT. Five OMT sessions were provided at weeks 0, 1, 2, 4, and 6, and the prevalence of each biomechanical dysfunction was again measured at week 8 immediately before the final OMT session. Moderate pain improvement (≥30% reduction on a 100-mm visual analogue scale) at week 12 defined a successful LBP response to treatment. Prevalence rates at baseline were: non-neutral lumbar dysfunction, 124 (54%); pubic shear, 191 (83%); innominate shear, 69 (30%); restricted sacral nutation, 87 (38%), and psoas syndrome, 117 (51%). Significant improvements in each biomechanical dysfunction were observed with OMT; however, only psoas syndrome remission occurred more frequently in LBP responders than non-responders (P for interaction = 0.002). Remission of psoas syndrome was the only change in biomechanical dysfunction that predicted subsequent LBP response after controlling for the other biomechanical dysfunctions and potential confounders (odds ratio, 5.11; 95% confidence interval, 1.54-16.96). These findings suggest that remission of psoas syndrome may be an important and previously unrecognized mechanism explaining clinical improvement in patients with chronic LBP following OMT.

PMID: 24704126 [PubMed - as supplied by publisher]