Recent Research Articles from UNTHSC

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Nanobiosensors: role in cancer detection and diagnosis.

Sun, 07/06/2014 - 4:04am
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Nanobiosensors: role in cancer detection and diagnosis.

Adv Exp Med Biol. 2014;807:33-58

Authors: Gdowski A, Ranjan AP, Mukerjee A, Vishwanatha JK

Abstract
The ability to detect many cancers at an early stage in its clinical course has the potential to improve patient outcomes in terms of morbidity and mortality. Nanosized components incorporated into existing clinical diagnostic and detection systems as well as novel nanobiosensors have demonstrated improved sensitivity and specificity compared with traditional cancer testing approaches. Nanoparticles, nanowires, nanotubes, and nanocantilevers are examples of four nanobiosensor systems that have been used experimentally in the context of detection and diagnosis of prostate, breast, pancreatic, lung, and brain cancers over the past few years. Nanobiosensors will begin to transition into clinically validated tests as experimental and engineering techniques advance. This paper presents examples of some such nanobiosensors for cancer diagnosis and detection.

PMID: 24619617 [PubMed - indexed for MEDLINE]

Acute Effects of Muscle Fatigue on Anticipatory and Reactive Postural Control in Older Individuals: A Systematic Review of the Evidence.

Wed, 07/02/2014 - 4:05am
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Acute Effects of Muscle Fatigue on Anticipatory and Reactive Postural Control in Older Individuals: A Systematic Review of the Evidence.

J Geriatr Phys Ther. 2014 Jun 27;

Authors: Papa EV, Garg H, Dibble LE

Abstract
BACKGROUND:: Falls are the leading cause of traumatic brain injury and fractures and the No. 1 cause of emergency department visits by older adults. Although declines in muscle strength and sensory function contribute to increased falls in older adults, skeletal muscle fatigue is often overlooked as an additional contributor to fall risk. In an effort to increase awareness of the detrimental effects of skeletal muscle fatigue on postural control, we sought to systematically review research studies examining this issue.
PURPOSE:: The specific purpose of this review was to provide a detailed assessment of how anticipatory and reactive postural control tasks are influenced by acute muscle fatigue in healthy older individuals.
METHODS:: An extensive search was performed using the CINAHL, Scopus, PubMed, SPORTDiscus, and AgeLine databases for the period from inception of each database to June 2013. This systematic review used standardized search criteria and quality assessments via the American Academy for Cerebral Palsy and Developmental Medicine Methodology to Develop Systematic Reviews of Treatment Interventions (2008 version, revision 1.2, AACPDM, Milwaukee, Wisconsin).
RESULTS:: A total of 334 citations were found. Six studies were selected for inclusion, whereas 328 studies were excluded from the analytical review. The majority of articles (5 of 6) utilized reactive postural control paradigms. All studies incorporated extrinsic measures of muscle fatigue, such as declines in maximal voluntary contraction or available active range of motion. The most common biomechanical postural control task outcomes were spatial measures, temporal measures, and end-points of lower extremity joint kinetics.
CONCLUSION:: On the basis of systematic review of relevant literature, it appears that muscle fatigue induces clear deteriorations in reactive postural control. A paucity of high-quality studies examining anticipatory postural control supports the need for further research in this area. These results should serve to heighten awareness regarding the potential negative effects of acute muscle fatigue on postural control and support the examination of muscle endurance training as a fall risk intervention in future studies.

PMID: 24978932 [PubMed - as supplied by publisher]

High-quality and high-throughput massively parallel sequencing of the human mitochondrial genome using the Illumina MiSeq.

Tue, 07/01/2014 - 4:05am
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High-quality and high-throughput massively parallel sequencing of the human mitochondrial genome using the Illumina MiSeq.

Forensic Sci Int Genet. 2014 Jun 7;12C:128-135

Authors: King JL, LaRue BL, Novroski NM, Stoljarova M, Seo SB, Zeng X, Warshauer DH, Davis CP, Parson W, Sajantila A, Budowle B

Abstract
Mitochondrial DNA typing in forensic genetics has been performed traditionally using Sanger-type sequencing. Consequently sequencing of a relatively-large target such as the mitochondrial genome (mtGenome) is laborious and time consuming. Thus, sequencing typically focuses on the control region due to its high concentration of variation. Massively parallel sequencing (MPS) has become more accessible in recent years allowing for high-throughput processing of large target areas. In this study, Nextera(®) XT DNA Sample Preparation Kit and the Illumina MiSeq™ were utilized to generate quality whole genome mitochondrial haplotypes from 283 individuals in a both cost-effective and rapid manner. Results showed that haplotypes can be generated at a high depth of coverage with limited strand bias. The distribution of variants across the mitochondrial genome was described and demonstrated greater variation within the coding region than the non-coding region. Haplotype and haplogroup diversity were described with respect to whole mtGenome and HVI/HVII. An overall increase in haplotype or genetic diversity and random match probability, as well as better haplogroup assignment demonstrates that MPS of the mtGenome using the Illumina MiSeq system is a viable and reliable methodology.

PMID: 24973578 [PubMed - as supplied by publisher]

Antigen-Pulsed Bone Marrow-Derived and Pulmonary Dendritic Cells Promote Th2 Cell Responses and Immunopathology in Lungs during the Pathogenesis of Murine Mycoplasma Pneumonia.

Tue, 07/01/2014 - 4:05am
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Antigen-Pulsed Bone Marrow-Derived and Pulmonary Dendritic Cells Promote Th2 Cell Responses and Immunopathology in Lungs during the Pathogenesis of Murine Mycoplasma Pneumonia.

J Immunol. 2014 Jun 27;

Authors: Dobbs NA, Zhou X, Pulse M, Hodge LM, Schoeb TR, Simecka JW

Abstract
Mycoplasmas are a common cause of pneumonia in humans and animals, and attempts to create vaccines have not only failed to generate protective host responses, but they have exacerbated the disease. Mycoplasma pulmonis causes a chronic inflammatory lung disease resulting from a persistent infection, similar to other mycoplasma respiratory diseases. Using this model, Th1 subsets promote resistance to mycoplasma disease and infection, whereas Th2 responses contribute to immunopathology. The purpose of the present study was to evaluate the capacity of cytokine-differentiated dendritic cell (DC) populations to influence the generation of protective and/or pathologic immune responses during M. pulmonis respiratory disease in BALB/c mice. We hypothesized that intratracheal inoculation of mycoplasma Ag-pulsed bone marrow-derived DCs could result in the generation of protective T cell responses during mycoplasma infection. However, intratracheal inoculation (priming) of mice with Ag-pulsed DCs resulted in enhanced pathology in the recipient mice when challenged with mycoplasma. Inoculation of immunodeficient SCID mice with Ag-pulsed DCs demonstrated that this effect was dependent on lymphocyte responses. Similar results were observed when mice were primed with Ag-pulsed pulmonary, but not splenic, DCs. Lymphocytes generated in uninfected mice after the transfer of either Ag-pulsed bone marrow-derived DCs or pulmonary DCs were shown to be IL-13(+) Th2 cells, known to be associated with immunopathology. Thus, resident pulmonary DCs most likely promote the development of immunopathology in mycoplasma disease through the generation of mycoplasma-specific Th2 responses. Vaccination strategies that disrupt or bypass this process could potentially result in a more effective vaccination.

PMID: 24973442 [PubMed - as supplied by publisher]

Cerebral Palsy of the Elbow and Forearm.

Sun, 06/29/2014 - 4:05am

Cerebral Palsy of the Elbow and Forearm.

J Hand Surg Am. 2014 Jul;39(7):1425-1432

Authors: Bunata R, Icenogle K

Abstract
Management of elbow and forearm involvement in cerebral palsy has evolved over the last 3 decades with a better understanding of its neuropathophysiology, improved outcome measures, and evolving therapy protocols. Current nonoperative and surgical treatment methods are discussed. The use of standard function measuring instruments and encouragement of the participation in research will hopefully result in more accurate outcome information and, thereby, refine our techniques and rehabilitation methods.

PMID: 24969499 [PubMed - as supplied by publisher]

Clinical response and relapse in patients with chronic low back pain following osteopathic manual treatment: Results from the OSTEOPATHIC Trial.

Sat, 06/28/2014 - 4:05am
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Clinical response and relapse in patients with chronic low back pain following osteopathic manual treatment: Results from the OSTEOPATHIC Trial.

Man Ther. 2014 Jun 5;

Authors: Licciardone JC, Aryal S

Abstract
Clinical response and relapse following a regimen of osteopathic manual treatment (OMT) were assessed in patients with chronic low back pain (LBP) within the OSTEOPATHIC Trial, a randomized, double-blind, sham-controlled study. Initial clinical response and subsequent stability of response, including final response and relapse status at week 12, were determined in 186 patients with high baseline pain severity (≥50 mm on a 100-mm visual analogue scale). Substantial improvement in LBP, defined as 50% or greater pain reduction relative to baseline, was used to assess clinical response at weeks 1, 2, 4, 6, 8, and 12. Sixty-two (65%) patients in the OMT group attained an initial clinical response vs. 41 (45%) patients in the sham OMT group (risk ratio [RR], 1.45; 95% confidence interval [CI], 1.11-1.90). The median time to initial clinical response to OMT in these patients was 4 weeks. Among patients with an initial clinical response prior to week 12, 13 (24%) patients in the OMT group vs. 18 (51%) patients in the sham OMT group relapsed (RR, 0.47; 95% CI, 0.26-0.83). Overall, 49 (52%) patients in the OMT group attained or maintained a clinical response at week 12 vs. 23 (25%) patients in the sham OMT group (RR, 2.04; 95% CI, 1.36-3.05). The large effect size for short-term efficacy of OMT was driven by stable responders who did not relapse.

PMID: 24965494 [PubMed - as supplied by publisher]

Mitigating prolonged QT interval in cancer nanodrug development for accelerated clinical translation.

Sat, 06/28/2014 - 4:05am
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Mitigating prolonged QT interval in cancer nanodrug development for accelerated clinical translation.

J Nanobiotechnology. 2013;11:40

Authors: Ranjan AP, Mukerjee A, Helson L, Vishwanatha JK

Abstract
BACKGROUND: Cardiac toxicity is the foremost reason for drug discontinuation from development to clinical evaluation and post market surveillance [Fung 35:293-317, 2001; Piccini 158:317-326 2009]. The Food and Drug Administration (FDA) has rejected many potential pharmaceutical agents due to QT prolongation effects. Since drug development and FDA approval takes an enormous amount of time, money and effort with high failure rates, there is an increased focus on rescuing drugs that cause QT prolongation. If these otherwise safe and potent drugs were formulated in a unique way so as to mitigate the QT prolongation associated with them, these potent drugs may get FDA approval for clinical use. Rescuing these compounds not only benefit the patients who need them but also require much less time and money thus leading to faster clinical translation. In this study, we chose curcumin as our drug of choice since it has been shown to posses anti-tumor properties against various cancers with limited toxicity. The major limitations with this pharmacologically active drug are (a) its ability to prolong QT by inhibiting the hERG channel and (b) its low bioavailability. In our previous studies, we found that lipids have protective actions against hERG channel inhibition and therefore QT prolongation.
RESULTS: Results of the manual patch clamp assay of HEK 293 cells clearly illustrated that our hybrid nanocurcumin formulation prevented the curcumin induced inhibition of hERG K+ channel at concentrations higher than the therapeutic concentrations of curcumin. Comparing the percent inhibition, the hybrid nanocurcumin limited inhibition to 24.8% at a high curcumin equivalent concentration of 18 μM. Liposomal curcumin could only decrease this inhibition upto 30% only at lower curcumin concentration of 6 μM but not at 18 μM concentration.
CONCLUSIONS: Here we show a curcumin encapsulated lipopolymeric hybrid nanoparticle formulation which could protect against QT prolongation and also render increased bioavailability and stability thereby overcoming the limitations associated with curcumin.

PMID: 24330336 [PubMed - indexed for MEDLINE]

Direction of post-prandial ghrelin response associated with cortisol response, perceived stress and anxiety, and self-reported coping and hunger in obese women.

Fri, 06/27/2014 - 4:05am
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Direction of post-prandial ghrelin response associated with cortisol response, perceived stress and anxiety, and self-reported coping and hunger in obese women.

Behav Brain Res. 2013 Nov 15;257:197-200

Authors: Sarker MR, Franks S, Caffrey J

Abstract
The neurobiological mechanisms modulating stress may share common pathways with appetite regulation and consequent obesity. The orexigenic hormone, ghrelin may moderate anxiety and stress-related eating behavior. This study was designed to investigate humoral (ghrelin, cortisol) and psychological/behavioral characteristics (subjective hunger, anxiety, and stress; eating behavior; coping ability) among obese subjects in a fasting state and after eating a standard meal. Subjects included 18 obese but otherwise healthy adult women. Subjects were divided into two groups based on the relative direction of ghrelin response to a standard meal. A meal mediated suppression in serum ghrelin (post/pre<.94) was defined as a normal ghrelin response (NG) (n=9) and failure to suppress (post/pre>1.0) was designated as faulty ghrelin response (FG) (n=9). Ghrelin and cortisol responses were correlated, r(18)=0.558, p=.016. FG subjects had lower ratings of coping ability [t(2,16)=2.437, p=.027 and higher ratings of hunger cues in the expected direction [t(2,16)=-2.061, p=.056] compared to NG subjects. Meal mediated declines in subjective hunger were observed for both NG [t(1,8)=4.141, p=.003] and FG [t(1,8)=2.718, p=.026]. NG also showed declines in subjective anxiety [t(1,8)=2.977, p=.018], subjective stress [t(1,8)=2.321, p=.049], and cortisol [t(1,8)=4.214, p=.003]. In conclusion, changes in ghrelin, cortisol and selected psychological and behavioral indices are closely associated with one another suggesting that ghrelin may influence stress related eating and thus, the consequent observed relationship among stress, mood and obesity.

PMID: 24099748 [PubMed - indexed for MEDLINE]

Notch1 signaling modulates neuronal progenitor activity in the subventricular zone in response to aging and focal ischemia.

Fri, 06/27/2014 - 4:05am
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Notch1 signaling modulates neuronal progenitor activity in the subventricular zone in response to aging and focal ischemia.

Aging Cell. 2013 Dec;12(6):978-87

Authors: Sun F, Mao X, Xie L, Ding M, Shao B, Jin K

Abstract
Neurogenesis diminishes with aging and ischemia-induced neurogenesis also occurs, but reduced in aged brain. Currently, the cellular and molecular pathways mediating these effects remain largely unknown. Our previous study has shown that Notch1 signaling regulates neurogenesis in subventricular zone (SVZ) of young adult brain after focal ischemia, but whether a similar effect occurs in aged normal and ischemic animals is unknown. Here, we used normal and ischemic aged rat brains to investigate whether Notch1 signaling was involved in the reduction of neurogenesis in response to aging and modulates neurogenesis in aged brains after focal ischemia. By Western blot, we found that Notch1 and Jagged1 expression in the SVZ of aged brain was significantly reduced compared with young adult brain. Consistently, the activated form of Notch1 (Notch intracellular domain; NICD) expression was also declined. Immunohistochemistry confirmed that expression and activation of Notch1 signaling in the SVZ of aged brain were reduced. Double or triple immunostaining showed that that Notch1 was mainly expressed in doublecortin (DCX)-positive cells, whereas Jagged1 was predominantly expressed in astroglial cells in the SVZ of normal aged rat brain. In addition, disruption or activation of Notch1 signaling altered the number of proliferating cells labeled by bromodeoxyuridine (BrdU) and DCX in the SVZ of aged brain. Moreover, ischemia-induced cell proliferation in the SVZ of aged brain was enhanced by activating the Notch1 pathway and was suppressed by inhibiting the Notch1 signaling. Reduced infarct volume and improved motor deficits were also observed in Notch1 activator-treated aged ischemic rats. Our data suggest that Notch1 signaling modulates the SVZ neurogenesis in aged brain in normal and ischemic conditions.

PMID: 23834718 [PubMed - indexed for MEDLINE]

Population data on 25 autosomal STRs for 500 unrelated Kuwaitis.

Thu, 06/26/2014 - 4:04am

Population data on 25 autosomal STRs for 500 unrelated Kuwaitis.

Forensic Sci Int Genet. 2014 Jun 2;12C:126-127

Authors: Al-Enizi M, Ge J, Salih A, Alenizi H, Al Jabber J, Ziab J, Al Harbi E, Isameal S, Budowle B

PMID: 24960412 [PubMed - as supplied by publisher]

MAPIT: development of a web-based intervention targeting substance abuse treatment in the criminal justice system.

Wed, 06/25/2014 - 4:04am
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MAPIT: development of a web-based intervention targeting substance abuse treatment in the criminal justice system.

J Subst Abuse Treat. 2014 Jan;46(1):60-5

Authors: Walters ST, Ondersma SJ, Ingersoll KS, Rodriguez M, Lerch J, Rossheim ME, Taxman FS

Abstract
Although drug and alcohol treatment are common requirements in the U.S. criminal justice system, only a minority of clients actually initiate treatment. This paper describes a two-session, web-based intervention to increase motivation for substance abuse treatment among clients using illicit substances. MAPIT (Motivational Assessment Program to Initiate Treatment) integrates the extended parallel process model, motivational interviewing, and social cognitive theory. The first session (completed near the start of probation) targets motivation to complete probation, to make changes in substance use (including treatment initiation), and to obtain HIV testing and care. The second session (completed approximately 30days after session 1) focuses on goal setting, coping strategies, and social support. Both sessions can generate emails or mobile texts to remind clients of their goals. MAPIT uses theory-based algorithms and a text-to-speech engine to deliver custom feedback and suggestions. In an initial test, participants indicated that the program was respectful, easy to use, and would be helpful in making changes in substance use. MAPIT is being tested in a randomized trial in two large U.S. probation agencies. MAPIT addresses the difficulties of many probation agencies to maximize client involvement in treatment, in a way that is cost effective and compatible with the existing service delivery system.

PMID: 23954392 [PubMed - indexed for MEDLINE]

mitoSAVE: Mitochondrial sequence analysis of variants in Excel.

Tue, 06/24/2014 - 4:04am
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mitoSAVE: Mitochondrial sequence analysis of variants in Excel.

Forensic Sci Int Genet. 2014 Jun 2;12C:122-125

Authors: King JL, Sajantila A, Budowle B

Abstract
The mitochondrial genome (mtGenome) contains genetic information amenable to numerous applications such as medical research, population and evolutionary studies, and human identity testing. However, inconsistent nomenclature assignment makes haplotype comparison difficult and can lead to false exclusion of potentially useful profiles. Massively Parallel Sequencing (MPS) is a platform for sequencing large datasets and potentially whole populations with relative ease. However, the data generated are not easily parsed and interpreted. With this in mind, mitoSAVE has been developed to enable fast conversion of Variant Call Format (VCF) files. mitoSAVE is an Excel-based workbook that converts data within the VCF into mtDNA haplotypes using phylogenetically-established nomenclature as well as rule-based alignments consistent with current forensic standards. mitoSAVE is formatted for human mitochondrial genome; however, it can easily be adapted to support other reasonably small genomes.

PMID: 24952129 [PubMed - as supplied by publisher]

Methamphetamine and HIV-1-induced neurotoxicity: Role of trace amine associated receptor 1 cAMP signaling in astrocytes.

Sun, 06/22/2014 - 4:04am

Methamphetamine and HIV-1-induced neurotoxicity: Role of trace amine associated receptor 1 cAMP signaling in astrocytes.

Neuropharmacology. 2014 Jun 17;

Authors: Cisneros IE, Ghorpade A

Abstract
Methamphetamine (METH) is abused by about 5% of the United States population with approximately 10-15% of human immunodeficiency virus-1 (HIV-1) patients reporting its use. METH abuse accelerates the onset and severity of HIV-associated neurocognitive disorders (HAND) and astrocyte-induced neurotoxicity. METH activates G-protein coupled receptors such as trace amine associated receptor 1 (TAAR1) increasing intracellular cyclic adenosine monophosphate (cAMP) levels in presynaptic cells of monoaminergic systems. In the present study, we investigated the effects of METH and HIV-1 on primary human astrocyte TAAR1 expression, function and glutamate clearance. Our results demonstrate combined conditions increased TAAR1 mRNA levels 7-fold and increased intracellular cAMP levels. METH and beta-phenylethylamine (β-PEA), known TAAR1 agonists, increased intracellular cAMP levels in astrocytes. Further, TAAR1 knockdown significantly reduced intracellular cAMP levels in response to METH/β-PEA, indicating signaling through astrocyte TAAR1. METH +/- HIV-1 decreased excitatory amino acid transporter-2 (EAAT-2) mRNA and significantly decreased glutamate clearance. RNA interference for TAAR1 prevented METH-mediated decreases in EAAT-2. TAAR1 knockdown significantly increased glutamate clearance, which was further heightened significantly by METH. Moreover, TAAR1 overexpression significantly decreased EAAT-2 levels and glutamate clearance that were further reduced by METH. Taken together, our data show that METH treatment activated TAAR1 leading to intracellular cAMP in human astrocytes and modulated glutamate clearance abilities. Furthermore, molecular alterations in astrocyte TAAR1 levels correspond to changes in astrocyte EAAT-2 levels and function. To our knowledge this is the first report implicating astrocyte TAAR1 as a novel receptor for METH during combined injury in the context of HAND.

PMID: 24950453 [PubMed - as supplied by publisher]

Caloric restriction and the aging process: a critique.

Sat, 06/21/2014 - 4:06am
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Caloric restriction and the aging process: a critique.

Free Radic Biol Med. 2014 Jun 2;

Authors: Sohal RS, Forster MJ

Abstract
The main objective of this review is to provide an appraisal of the current status of the relationship between energy intake and the life span of animals. The concept that a reduction in food intake, or caloric restriction (CR), retards the aging process, delays the age-associated decline in physiological fitness, and extends the life span of organisms of diverse phylogenetic groups is one of the leading paradigms in gerontology. However, emerging evidence disputes some of the primary tenets of this conception. One disparity is that the CR-related increase in longevity is not universal and may not even be shared among different strains of the same species. A further misgiving is that the control animals, fed ad libitum (AL), become overweight and prone to early onset of diseases and death, and thus may not be the ideal control animals for studies concerned with comparisons of longevity. Reexamination of body weight and longevity data from a study involving over 60,000 mice and rats, conducted by a National Institute on Aging-sponsored project, suggests that CR-related increase in life span of specific genotypes is directly related to the gain in body weight under the AL feeding regimen. Additionally, CR in mammals and "dietary restriction" in organisms such as Drosophila are dissimilar phenomena, albeit they are often presented to be the very same. The latter involves a reduction in yeast rather than caloric intake, which is inconsistent with the notion of a common, conserved mechanism of CR action in different species. Although specific mechanisms by which CR affects longevity are not well understood, existing evidence supports the view that CR increases the life span of those particular genotypes that develop energy imbalance owing to AL feeding. In such groups, CR lowers body temperature, rate of metabolism, and oxidant production and retards the age-related pro-oxidizing shift in the redox state.

PMID: 24941891 [PubMed - as supplied by publisher]

High glucose and diabetes enhanced store-operated Ca(2+) entry and increased expression of its signaling proteins in mesangial cells.

Sat, 06/21/2014 - 4:06am
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High glucose and diabetes enhanced store-operated Ca(2+) entry and increased expression of its signaling proteins in mesangial cells.

Am J Physiol Renal Physiol. 2014 May 1;306(9):F1069-80

Authors: Chaudhari S, Wu P, Wang Y, Ding Y, Yuan J, Begg M, Ma R

Abstract
The present study was conducted to determine whether and how store-operated Ca(2+) entry (SOCE) in glomerular mesangial cells (MCs) was altered by high glucose (HG) and diabetes. Human MCs were treated with either normal glucose or HG for different time periods. Cyclopiazonic acid-induced SOCE was significantly greater in the MCs with 7-day HG treatment and the response was completely abolished by GSK-7975A, a selective inhibitor of store-operated Ca(2+) channels. Similarly, the inositol 1,4,5-trisphosphate-induced store-operated Ca(2+) currents were significantly enhanced in the MCs treated with HG for 7 days, and the enhanced response was abolished by both GSK-7975A and La(3+). In contrast, receptor-operated Ca(2+) entry in MCs was significantly reduced by HG treatment. Western blotting showed that HG increased the expression levels of STIM1 and Orai1 in cultured MCs. A significant HG effect occurred at a concentration as low as 10 mM, but required a minimum of 7 days. The HG effect in cultured MCs was recapitulated in renal glomeruli/cortex of both type I and II diabetic rats. Furthermore, quantitative real-time RT-PCR revealed that a 6-day HG treatment significantly increased the mRNA expression level of STIM1. However, the expressions of STIM2 and Orai1 transcripts were not affected by HG. Taken together, these results suggest that HG/diabetes enhanced SOCE in MCs by increasing STIM1/Orai1 protein expressions. HG upregulates STIM1 by promoting its transcription but increases Orai1 protein through a posttranscriptional mechanism.

PMID: 24623143 [PubMed - indexed for MEDLINE]

Role of the p63-FoxN1 regulatory axis in thymic epithelial cell homeostasis during aging.

Fri, 06/20/2014 - 4:05am
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Role of the p63-FoxN1 regulatory axis in thymic epithelial cell homeostasis during aging.

Cell Death Dis. 2013;4:e932

Authors: Burnley P, Rahman M, Wang H, Zhang Z, Sun X, Zhuge Q, Su DM

Abstract
The p63 gene regulates thymic epithelial cell (TEC) proliferation, whereas FoxN1 regulates their differentiation. However, their collaborative role in the regulation of TEC homeostasis during thymic aging is largely unknown. In murine models, the proportion of TAp63(+), but not ΔNp63(+), TECs was increased with age, which was associated with an age-related increase in senescent cell clusters, characterized by SA-β-Gal(+) and p21(+) cells. Intrathymic infusion of exogenous TAp63 cDNA into young wild-type (WT) mice led to an increase in senescent cell clusters. Blockade of TEC differentiation via conditional FoxN1 gene knockout accelerated the appearance of this phenotype to early middle age, whereas intrathymic infusion of exogenous FoxN1 cDNA into aged WT mice brought only a modest reduction in the proportion of TAp63(+) TECs, but an increase in ΔNp63(+) TECs in the partially rejuvenated thymus. Meanwhile, we found that the increased TAp63(+) population contained a high proportion of phosphorylated-p53 TECs, which may be involved in the induction of cellular senescence. Thus, TAp63 levels are positively correlated with TEC senescence but inversely correlated with expression of FoxN1 and FoxN1-regulated TEC differentiation. Thereby, the p63-FoxN1 regulatory axis in regulation of postnatal TEC homeostasis has been revealed.

PMID: 24263106 [PubMed - indexed for MEDLINE]

Nanoparticle-mediated catalase delivery protects human neurons from oxidative stress.

Fri, 06/20/2014 - 4:05am
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Nanoparticle-mediated catalase delivery protects human neurons from oxidative stress.

Cell Death Dis. 2013;4:e903

Authors: Singhal A, Morris VB, Labhasetwar V, Ghorpade A

Abstract
Several neurodegenerative diseases and brain injury involve reactive oxygen species and implicate oxidative stress in disease mechanisms. Hydrogen peroxide (H2O2) formation due to mitochondrial superoxide leakage perpetuates oxidative stress in neuronal injury. Catalase, an H2O2-degrading enzyme, thus remains an important antioxidant therapy target. However, catalase therapy is restricted by its labile nature and inadequate delivery. Here, a nanotechnology approach was evaluated using catalase-loaded, poly(lactic co-glycolic acid) nanoparticles (NPs) in human neuronal protection against oxidative damage. This study showed highly efficient catalase encapsulation capable of retaining ~99% enzymatic activity. NPs released catalase rapidly, and antioxidant activity was sustained for over a month. NP uptake in human neurons was rapid and nontoxic. Although human neurons were highly sensitive to H2O2, NP-mediated catalase delivery successfully protected cultured neurons from H2O2-induced oxidative stress. Catalase-loaded NPs significantly reduced H2O2-induced protein oxidation, DNA damage, mitochondrial membrane transition pore opening and loss of cell membrane integrity and restored neuronal morphology, neurite network and microtubule-associated protein-2 levels. Further, catalase-loaded NPs improved neuronal recovery from H2O2 pre-exposure better than free catalase, suggesting possible applications in ameliorating stroke-relevant oxidative stress. Brain targeting of catalase-loaded NPs may find wide therapeutic applications for oxidative stress-associated acute and chronic neurodegenerative disorders.

PMID: 24201802 [PubMed - indexed for MEDLINE]

Combining Select Neuropsychological Assessment with Blood-Based Biomarkers to Detect Mild Alzheimer's Disease: A Molecular Neuropsychology Approach.

Fri, 06/13/2014 - 4:04am
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Combining Select Neuropsychological Assessment with Blood-Based Biomarkers to Detect Mild Alzheimer's Disease: A Molecular Neuropsychology Approach.

J Alzheimers Dis. 2014 Jun 10;

Authors: Edwards M, Balldin VH, Hall J, O'Bryant S

Abstract
Background: Current work has sought to establish a rapid and cost effective means of screening for Alzheimer's disease (AD) with the most recent findings showing utility of integrating blood-based biomarkers with cognitive measures. Objective: The current project sought to create a combined biomarker-cognitive profile to detect mild AD. Methods: Data was analyzed from 266 participants (129 AD cases [Early AD n = 93; Very Early AD n = 36]; 137 controls) enrolled in the Texas Alzheimer's Research and Care Consortium (TARCC). Non-fasting serum samples were collected from each participant and assayed via a multi-plex biomarker assay platform using electrochemiluminescence. Logistic Regression was utilized to detect early AD using two serum biomarkers (TNFα and IL7), demographic information (age), and one neuropsychological measure (Clock 4-point) as predictor variable. Disease severity was determined via Clinical Dementia Rating (CDR) scale global scores. Results: In the total sample (all levels of CDR scores), the combination of biomarkers, cognitive test score, and demographics yielded the obtained sensitivity (SN) of 0.94, specificity (SP) of 0.90, and an overall accuracy of 0.92. When examining early AD cases (i.e.m CDR = 0.5-1), the biomarker-cognitive profile yielded SN of 0.94, SP of 0.85, and an overall accuracy of 0.91. When restricted to very early AD cases (i.e., CDR = 0.5), the biomarker-cognitive profile yielded SN of 0.97 and SP of 0.72, with an overall accuracy of 0.91. Conclusions: The combination of demographics, two biomarkers, and one cognitive test created a biomarker-cognitive profile that was highly accurate in detecting the presence of AD, even in the very early stages.

PMID: 24916542 [PubMed - as supplied by publisher]

Rad5 template switch pathway of DNA damage tolerance determines synergism between cisplatin and NSC109268 in Saccharomyces cerevisiae.

Fri, 06/13/2014 - 4:04am
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Rad5 template switch pathway of DNA damage tolerance determines synergism between cisplatin and NSC109268 in Saccharomyces cerevisiae.

PLoS One. 2013;8(10):e77666

Authors: Jain D, Siede W

Abstract
The success of cisplatin (CP) based therapy is often hindered by acquisition of CP resistance. We isolated NSC109268 as a compound altering cellular sensitivity to DNA damaging agents. Previous investigation revealed an enhancement of CP sensitivity by NSC109268 in wild-type Saccharomyces cerevisiae and CP-sensitive and -resistant cancer cell lines that correlated with a slower S phase traversal. Here, we extended these studies to determine the target pathway(s) of NSC109268 in mediating CP sensitization, using yeast as a model. We reasoned that mutants defective in the relevant target of NSC109268 should be hypersensitive to CP and the sensitization effect by NSC109268 should be absent or strongly reduced. A survey of various yeast deletion mutants converged on the Rad5 pathway of DNA damage tolerance by template switching as the likely target pathway of NSC109268 in mediating cellular sensitization to CP. Additionally, cell cycle delays following CP treatment were not synergistically influenced by NSC109268 in the CP hypersensitive rad5Δ mutant. The involvement of the known inhibitory activities of NSC109268 on 20S proteasome and phosphatases 2Cα and 2A was tested. In the CP hypersensitive ptc2Δptc3Δpph3Δ yeast strain, deficient for 2C and 2A-type phosphatases, cellular sensitization to CP by NSC109268 was greatly reduced. It is therefore suggested that NSC109268 affects CP sensitivity by inhibiting the activity of unknown protein(s) whose dephosphorylation is required for the template switch pathway.

PMID: 24130896 [PubMed - indexed for MEDLINE]

American Society of Biomechanics Clinical Biomechanics Award 2012: plantar shear stress distributions in diabetic patients with and without neuropathy.

Thu, 06/12/2014 - 4:04am
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American Society of Biomechanics Clinical Biomechanics Award 2012: plantar shear stress distributions in diabetic patients with and without neuropathy.

Clin Biomech (Bristol, Avon). 2014 Feb;29(2):223-9

Authors: Yavuz M

Abstract
BACKGROUND: The exact pathology of diabetic foot ulcers remains to be resolved. Evidence suggests that plantar shear forces play a major role in diabetic ulceration. Unfortunately, only a few manuscripts exist on the clinical implications of plantar shear. The purpose of this study was to compare global and regional peak plantar stress values in three groups; diabetic patients with neuropathy, diabetic patients without neuropathy and healthy control subjects.
METHODS: Fourteen diabetic neuropathic patients, 14 non-neuropathic diabetic control and 11 non-diabetic control subjects were recruited. Subjects walked on a custom-built stress plate that quantified plantar pressures and shear. Four stress variables were analyzed; peak pressure, peak shear, peak pressure-time and shear-time integral.
FINDINGS: Global peak values of peak shear (p = 0.039), shear-time integral (p = 0.002) and pressure-time integral (p = 0.003) were significantly higher in the diabetic neuropathic group. The local peak shear stress and shear-time integral were also significantly higher in diabetic neuropathic patients compared to both control groups, in particular, at the hallux and central forefoot. The local peak pressure and pressure-time integral were significantly different between the three groups at the medial and lateral forefoot.
INTERPRETATION: Plantar shear and shear-time integral magnitudes were elevated in diabetic patients with peripheral neuropathy, which indicates the potential clinical significance of these factors in ulceration. It is thought that further investigation of plantar shear would lead to a better understanding of ulceration pathomechanics, which in turn will assist researchers in developing more effective preventive devices and strategies.

PMID: 24332719 [PubMed - indexed for MEDLINE]