Recent Research Articles from UNTHSC

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Development of biodegradable nanocarriers loaded with a monoclonal antibody.

Tue, 12/15/2015 - 11:13
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Development of biodegradable nanocarriers loaded with a monoclonal antibody.

Int J Mol Sci. 2015;16(2):3990-5

Authors: Gdowski A, Ranjan A, Mukerjee A, Vishwanatha J

Abstract
Treatments utilizing monoclonal antibody therapeutics against intracellular protein-protein interactions in cancer cells have been hampered by several factors, including poor intracellular uptake and rapid lysosomal degradation. Our current work examines the feasibility of encapsulating monoclonal antibodies within poly(lactic-co-glycolic acid) (PLGA) nanoparticles using a water/oil/water double emulsion solvent evaporation technique. This method can be used to prepare protective polymeric nanoparticles for transporting functional antibodies to the cytoplasmic compartment of cancer cells. Nanoparticles were formulated and then characterized using a number of physical and biological parameters. The average nanoparticle size ranged from 221 to 252 nm with a low polydispersity index. Encapsulation efficiency of 16%-22% and antibody loading of 0.3%-1.12% were observed. The antibody molecules were released from the nanoparticles in a sustained manner and upon release maintained functionality. Our studies achieved successful formulation of antibody loaded polymeric nanoparticles, thus indicating that a PLGA-based antibody nanoformulation is a promising intracellular delivery vehicle for a large number of new intracellular antibody targets in cancer cells.

PMID: 25690029 [PubMed - indexed for MEDLINE]

Cancer mortality in the meat and delicatessen departments of supermarkets (1950-2006).

Tue, 12/15/2015 - 11:13
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Cancer mortality in the meat and delicatessen departments of supermarkets (1950-2006).

Environ Int. 2015 Apr;77:70-5

Authors: Johnson ES, Cardarelli K, Jadhav S, Chedjieu IP, Faramawi M, Fischbach L, Ndetan H, Wells TL, Patel KV, Katyal A

Abstract
Meat cutters and meat wrappers in the meat department of supermarkets are exposed to oncogenic viruses present in raw meat from cattle, pigs, sheep, and poultry, and their products (unpasteurized milk and raw eggs). Up to the mid 1970s, meat wrappers were also exposed to carcinogens present in fumes emitted from the machine used to wrap meat. Because of this we studied cancer mortality in a cohort of 10,701 workers in the meat and delicatessen departments of supermarkets, and we report here the findings after the third follow-up. Standardized mortality ratios (SMR) were estimated in the cohort as a whole and in race/sex subgroups, using the US population for comparison. Study subjects were followed up from January 1950 to December 2006. Significantly increased SMRs of 1.3 (95% CI, 1.2-1.5), and 2.7 (95% CI, 1.2-5.3) were recorded for cancers of the lung, and tonsils/oropharynx, respectively, in the entire cohort, affecting nearly all race/sex subgroups. SMRs of 4.6 (95% CI, 1.0-13.6) for cancer of the floor of the mouth, and 2.8 (95% CI, 1.3-5.3) for cancer of the gall bladder and biliary tract were recorded only in White male meatcutters. Significantly decreased SMRs were observed for a few cancers. It is not known if the observed excess of cancers is a result of occupational exposures. However, substantial evidence points to fumes from the wrapping machine as a possible candidate for explaining the excess in female meat wrappers. Nested case-control studies that can examine risks from occupational exposures in greater detail, and adequately control for confounding factors are now needed, to permit specifically investigate the role of the oncogenic viruses, fumes and non-occupational risk factors in the occurrence of these cancers. The findings are important, not only occupationally but also because the general population may also experience these exposures, albeit to a lesser degree.

PMID: 25656684 [PubMed - indexed for MEDLINE]

STAT3 and its phosphorylation are involved in HIV-1 Tat-induced transactivation of glial fibrillary acidic protein.

Tue, 12/15/2015 - 11:13
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STAT3 and its phosphorylation are involved in HIV-1 Tat-induced transactivation of glial fibrillary acidic protein.

Curr HIV Res. 2015;13(1):55-63

Authors: Fan Y, Timani KA, He JJ

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

PMID: 25613134 [PubMed - indexed for MEDLINE]

Lenticular cytoprotection, part 2: link between glycogen synthase kinase-3β, epithelial to mesenchymal transition, and mitochondrial depolarization.

Tue, 12/15/2015 - 11:13
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Lenticular cytoprotection, part 2: link between glycogen synthase kinase-3β, epithelial to mesenchymal transition, and mitochondrial depolarization.

Mol Vis. 2014;20:1758-75

Authors: Neelam S, Brooks MM, Cammarata PR

Abstract
PURPOSE: The inhibition of GSK-3β blocks mitochondrial membrane permeability transition (mMPT) for HLE-B3 cells in atmospheric oxygen. GSK-3β, as part of a multifactorial complex, also regulates nuclear levels of β-catenin, a known coordinator of cell survival and adhesion. The purpose of these studies was to demonstrate a novel, but likely disadvantageous, link between β-catenin's influence on the expression of the pro-survival protein, vascular endothelial growth factor (VEGF), resulting in enhanced lens epithelial cell mitochondrial protection against depolarization and nuclear β-catenin as an inducer of epithelial to mesenchymal transition (EMT).
METHODS: Virally transformed human lens epithelial cells (HLE-B3) were treated with SB216763, a specific inhibitor of GSK-3β catalytic activity and XAV939, a specific β-catenin inhibitor that bars the translocation of β-catenin from cytoplasm to the nucleus. Western blot analysis was employed to detect the levels of cytoplasmic and nuclear β-catenin and phospho-β-catenin, pBcl-2 and the EMT proteins, α-smooth muscle actin (α-SMA), and fibronectin. ELISA was used to measure the levels of VEGF in cell culture supernatants. JC-1 analysis was performed to analyze the influence of either SB216763 or XAV939 on mitochondrial depolarization.
RESULTS: Cultured lens epithelial cells maintained in hypoxia (1% oxygen) and subsequently reintroduced into atmospheric oxygen and treated with the GSK-3β inhibitor SB216763 illustrated a marked inhibition of phosphorylation of glycogen synthase (downstream substrate of GSK-3β) and significant increase in nuclear translocation of β-catenin. The augmented nuclear β-catenin levels positively correlated with increased expression of α-SMA and fibronectin, both marker proteins indicative of EMT. The enhanced nuclear β-catenin activity also elicited increased VEGF and pBcl-2 expression, resulting in increased resistance to mitochondrial depolarization. Treatment of the cells with the β-catenin inhibitor XAV939 resulted in decreased expression of nuclear β-catenin, VEGF levels, pBcl-2, and EMT proteins, as well as increased mitochondrial depolarization.
CONCLUSIONS: The data support a model whereby the onset of epithelial to mesenchymal transition may circuitously benefit from the enhanced synthesis of VEGF by setting up a potentially harmful situation whereby the resulting mesenchymal cell population may be more resistant to mitochondrial depolarization than the lens epithelial cell population from which it originated. These findings support the potential therapeutic relevance of developing strategies to undermine the progression of normal cells to mesenchymal transition without subverting cell viability.

PMID: 25593505 [PubMed - indexed for MEDLINE]

Selection of highly informative SNP markers for population affiliation of major US populations.

Thu, 12/10/2015 - 07:29
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Selection of highly informative SNP markers for population affiliation of major US populations.

Int J Legal Med. 2015 Dec 8;

Authors: Zeng X, Chakraborty R, King JL, LaRue B, Moura-Neto RS, Budowle B

Abstract
Ancestry informative markers (AIMs) can be used to detect and adjust for population stratification and predict the ancestry of the source of an evidence sample. Autosomal single nucleotide polymorphisms (SNPs) are the best candidates for AIMs. It is essential to identify the most informative AIM SNPs across relevant populations. Several informativeness measures for ancestry estimation have been used for AIMs selection: absolute allele frequency differences (δ), F statistics (F ST), and informativeness for assignment measure (In). However, their efficacy has not been compared objectively, particularly for determining affiliations of major US populations. In this study, these three measures were directly compared for AIMs selection among four major US populations, i.e., African American, Caucasian, East Asian, and Hispanic American. The results showed that the F ST panel performed slightly better for population resolution based on principal component analysis (PCA) clustering than did the δ panel and both performed better than the In panel. Therefore, the 23 AIMs selected by the F ST measure were used to characterize the four major American populations. Genotype data of nine sample populations were used to evaluate the efficiency of the 23-AIMs panel. The results indicated that individuals could be correctly assigned to the major population categories. Our AIMs panel could contribute to the candidate pool of AIMs for potential forensic identification purposes.

PMID: 26645290 [PubMed - as supplied by publisher]

Assessment of oral hygiene habits, oral hygiene practices and tooth wear among fertilizer factory workers of Northern India: A Cross sectional study.

Wed, 12/09/2015 - 07:30
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Assessment of oral hygiene habits, oral hygiene practices and tooth wear among fertilizer factory workers of Northern India: A Cross sectional study.

J Clin Exp Dent. 2015 Dec;7(5):e649-e655

Authors: Gupta VV, Asawa K, Bhat N, Tak M, Bapat S, Chaturvedi P, Philip-George P, Chitkara N, Patel MN, Shinde K, Sidhu PK

Abstract
BACKGROUND: The association between oral hygiene habits & practices and severity of tooth wear lesion varies from community to community and also from occupation to occupation. The present study was conducted with to assess oral hygiene habits & practices and tooth wear among fertilizer factory workers of Punjab, India.
MATERIAL AND METHODS: A descriptive cross sectional survey was conducted among 965 male workers who were aged between 19-58 years, who were the workers of fertilizers factory of Bathinda, India. An interview on the demographic profile, oral hygiene practices, and adverse habits followed a clinical examination for recording the Tooth Wear (Smith and Knight Index 1984) using Type III examination. The Chi-square test and a Stepwise multiple linear regression analysis were used for the statistical analysis. Confidence interval and p-value set at 95% and ≤ 0.05 respectively.
RESULTS: In the present study majority (47.2%) of the study population used chew sticks for cleaning their teeth. Overall prevalence of adverse habits was reported (92.4%). Study population showed higher prevalence of tooth wear (77.1%). Best predictors identified for Tooth Wear were oral hygiene practices, adverse habits, years of work experience and age respectively.
CONCLUSIONS: Considerable percentages of fertilizer factory workers have demonstrated a higher prevalence of tooth surface loss. This may be useful in designing the investigations that aim to further explore the causes for these findings and more importantly to plan oral health promotion program implementing both preventive and curative strategies. Key words:Tooth wear, smith & knight index, fertilizer factory.

PMID: 26644843 [PubMed - as supplied by publisher]

Engineered Production of Tryprostatins in E. coli through Reconstitution of a Partial ftm Biosynthetic Gene Cluster from Aspergillus sp.

Tue, 12/08/2015 - 07:29
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Engineered Production of Tryprostatins in E. coli through Reconstitution of a Partial ftm Biosynthetic Gene Cluster from Aspergillus sp.

Jacobs J Biotechnol Bioeng. 2015 Apr;2(1)

Authors: Shah GR, Wesener SR, Cheng YQ

Abstract
Tryprostatin A and B are indole alkaloid-based fungal products that inhibit mammalian cell cycle at the G2/M phase. They are biosynthetic intermediates of fumitremorgins produced by a complex pathway involving a nonribosomal peptide synthetase (FtmA), a prenyltransferase (FtmB), a cytochrome P450 hydroxylase (FtmC), an O-methyltransferase (FtmD), and several additional enzymes. A partial fumitremorgin biosynthetic gene cluster (ftmABCD) from Aspergillus sp. was reconstituted in Escherichia coli BL21(DE3) cells, with or without the co-expression of an Sfp-type phosphopantetheinyltransferase gene (Cv_sfp) from Chromobacterium violaceum No. 968. Several recombinant E. coli strains produced tryprostatin B up to 106 mg/l or tryprostatin A up to 76 mg/l in the fermentation broth under aerobic condition, providing an effective way to prepare those pharmaceutically important natural products biologically.

PMID: 26640821 [PubMed - as supplied by publisher]

The Management of Diabetic Foot Ulcers with Porcine Small Intestine Submucosa Tri-Layer Matrix: A Randomized Controlled Trial.

Fri, 12/04/2015 - 07:15
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The Management of Diabetic Foot Ulcers with Porcine Small Intestine Submucosa Tri-Layer Matrix: A Randomized Controlled Trial.

Adv Wound Care (New Rochelle). 2015 Dec 1;4(12):711-718

Authors: Cazzell SM, Lange DL, Dickerson JE, Slade HB

Abstract
Objective: This study demonstrates that superior outcomes are possible when diabetic foot ulcers (DFU) are managed with tri-layer porcine small intestine submucosa (SIS). Approach: Patients with DFU from 11 centers participated in this prospective randomized controlled trial. Qualified subjects were randomized (1:1) to either SIS or standard care (SC) selected at the discretion of the Investigator and followed for 12 weeks or complete ulcer closure. Results: Eighty-two subjects (41 in each group) were evaluable in the intent-to-treat analysis. Ulcers managed with SIS had a significantly greater proportion closed by 12 weeks than for the Control group (54% vs. 32%, p=0.021) and this proportion was numerically higher at all visits. Time to closure for ulcers achieving closure was 2 weeks earlier for the SIS group than for SC. Median reduction in ulcer area was significantly greater for SIS at each weekly visit (all p values<0.05). Review of reported adverse events found no safety concerns. Innovation: These data support the use of tri-layer SIS for the effective management of DFU. Conclusion: In this randomized controlled trial, SIS was found to be associated with more rapid improvement, and a higher likelihood of achieving complete ulcer closure than those ulcers treated with SC.

PMID: 26634183 [PubMed - as supplied by publisher]

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

Fri, 12/04/2015 - 07:15
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Target engagement and drug residence time can be observed in living cells with BRET.

Nat Commun. 2015;6:10091

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

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

PMID: 26631872 [PubMed - in process]

Managing Spaghetti Syndrome in Critical Care With a Novel Device: A Nursing Perspective.

Thu, 12/03/2015 - 07:29
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Managing Spaghetti Syndrome in Critical Care With a Novel Device: A Nursing Perspective.

Crit Care Nurse. 2015 Dec;35(6):38-45

Authors: Haynes J, Bowers K, Young R, Sanders T, Schultz KE

Abstract
BACKGROUND: Managing "spaghetti syndrome," the tangle of therapeutic cables, tubes, and cords at patients' bedsides, can be challenging.
OBJECTIVES: To assess nurses' perceptions of the effectiveness of a novel banding device in management of spaghetti syndrome.
METHODS: A simple color-coded elastomeric banding strap with ribbed flaps was attached to bed rails of adult critical care patients to help organize therapeutic cables, tubes, wires, and cords. Nurses were surveyed before and after use of the bands and after the nursing shift to assess the burden of spaghetti syndrome and the effectiveness of using the bands.
RESULTS: Use of the bands decreased the time spent untangling cords, reduced the frequency of contact of tubing with the floor, and diminished disruptions in care.
CONCLUSIONS: Use of a simple flexible latex-free elastomeric band may help organize therapeutic tubing at patients' bedsides and may promote improvements in nursing care.

PMID: 26628544 [PubMed - in process]

Can Genetic Analysis of Putative Blood Alzheimer's Disease Biomarkers Lead to Identification of Susceptibility Loci?

Wed, 12/02/2015 - 07:30
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Can Genetic Analysis of Putative Blood Alzheimer's Disease Biomarkers Lead to Identification of Susceptibility Loci?

PLoS One. 2015;10(12):e0142360

Authors: Barber RC, Phillips NR, Tilson JL, Huebinger RM, Shewale SJ, Koenig JL, Mitchel JS, O'Bryant SE, Waring SC, Diaz-Arrastia R, Chasse S, Wilhelmsen KC, Alzheimer’s Disease Neuroimaging Initiative and the Texas Alzheimer’s Research and Care Consortium

Abstract
Although 24 Alzheimer's disease (AD) risk loci have been reliably identified, a large portion of the predicted heritability for AD remains unexplained. It is expected that additional loci of small effect will be identified with an increased sample size. However, the cost of a significant increase in Case-Control sample size is prohibitive. The current study tests whether exploring the genetic basis of endophenotypes, in this case based on putative blood biomarkers for AD, can accelerate the identification of susceptibility loci using modest sample sizes. Each endophenotype was used as the outcome variable in an independent GWAS. Endophenotypes were based on circulating concentrations of proteins that contributed significantly to a published blood-based predictive algorithm for AD. Endophenotypes included Monocyte Chemoattractant Protein 1 (MCP1), Vascular Cell Adhesion Molecule 1 (VCAM1), Pancreatic Polypeptide (PP), Beta2 Microglobulin (B2M), Factor VII (F7), Adiponectin (ADN) and Tenascin C (TN-C). Across the seven endophenotypes, 47 SNPs were associated with outcome with a p-value ≤1x10-7. Each signal was further characterized with respect to known genetic loci associated with AD. Signals for several endophenotypes were observed in the vicinity of CR1, MS4A6A/MS4A4E, PICALM, CLU, and PTK2B. The strongest signal was observed in association with Factor VII levels and was located within the F7 gene. Additional signals were observed in MAP3K13, ZNF320, ATP9B and TREM1. Conditional regression analyses suggested that the SNPs contributed to variation in protein concentration independent of AD status. The identification of two putatively novel AD loci (in the Factor VII and ATP9B genes), which have not been located in previous studies despite massive sample sizes, highlights the benefits of an endophenotypic approach for resolving the genetic basis for complex diseases. The coincidence of several of the endophenotypic signals with known AD loci may point to novel genetic interactions and should be further investigated.

PMID: 26625115 [PubMed - as supplied by publisher]

Limb Ischemic Perconditioning Attenuates Blood-Brain Barrier Disruption by Inhibiting Activity of MMP-9 and Occludin Degradation after Focal Cerebral Ischemia.

Tue, 12/01/2015 - 07:29
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Limb Ischemic Perconditioning Attenuates Blood-Brain Barrier Disruption by Inhibiting Activity of MMP-9 and Occludin Degradation after Focal Cerebral Ischemia.

Aging Dis. 2015 Nov;6(6):406-417

Authors: Ren C, Li N, Wang B, Yang Y, Gao J, Li S, Ding Y, Jin K, Ji X

Abstract
Remote ischemic perconditioning (PerC) has been proved to have neuroprotective effects on cerebral ischemia, however, the effect of PerC on the BBB disruption and underlying mechanisms remains largely unknown. To address these issues, total 90 adult male Sprague Dawley (SD) rats were used. The rats underwent 90-min middle cerebral artery occlusion (MCAO), and the limb remote ischemic PerC was immediately applied after the onset of MCAO. We found that limb remote PerC protected BBB breakdown and brain edema, in parallel with reduced infarct volume and improved neurological deficits, after MCAO. Immunofluorescence studies revealed that MCAO resulted in disrupted continuity of claudin-5 staining in the cerebral endothelial cells with significant gap formation, which was significantly improved after PerC. Western blot analysis demonstrated that expression of tight junction (TJ) protein occludin was significantly increased, but other elements of TJ proteins, claudin-5 and ZO-1, in the BBB endothelial cells were not altered at 48 h after PerC, compared to MCAO group. The expression of matrix metalloproteinase (MMP-9), which was involved in TJ protein degradation, was decreased after PerC. Interestingly, phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2), an upstream of MMP-9 signaling, was significantly reduced in the PerC group. Our data suggest that PerC inhibits MMP-9-mediated occludin degradation, which could lead to decreased BBB disruption and brain edema after ischemic stroke.

PMID: 26618042 [PubMed - as supplied by publisher]

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

Sat, 11/28/2015 - 06:45

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

Ann Hum Genet. 2015 Nov 27;

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 - as supplied by publisher]

Initiation of calorie restriction in middle-aged male rats attenuates aging-related motoric decline and bradykinesia without increased striatal dopamine.

Sat, 11/28/2015 - 06:45

Initiation of calorie restriction in middle-aged male rats attenuates aging-related motoric decline and bradykinesia without increased striatal dopamine.

Neurobiol Aging. 2015 Oct 19;

Authors: Salvatore MF, Terrebonne J, Fields V, Nodurft D, Runfalo C, Latimer B, Ingram DK

Abstract
Aging-related bradykinesia affects ∼15% of those reaching age 65 and 50% of those reaching their 80s. Given this high risk and lack of pharmacologic therapeutics, noninvasive lifestyle strategies should be identified to diminish its risk and identify the neurobiological targets to reduce aging-related bradykinesia. Early-life, long-term calorie restriction (CR) attenuates aging-related bradykinesia in rodents. Here, we addressed whether CR initiation at middle age could attenuate aging-related bradykinesia and motoric decline measured as rotarod performance. A 30% CR regimen was implemented for 6 months duration in 12-month-old male Brown-Norway Fischer 344 F1 hybrid rats after establishing individual baseline locomotor activities. Locomotor capacity was assessed every 6 weeks thereafter. The ad libitum group exhibited predictably decreased locomotor activity, except movement speed, out to 18 months of age. In contrast, in the CR group, movement number and horizontal activity did not decrease during the 6-month trial, and aging-related decline in rotarod performance was attenuated. The response to CR was influenced by baseline locomotor activity. The lower the locomotor activity level at baseline, the greater the response to CR. Rats in the lower 50th percentile surpassed their baseline level of activity, whereas rats in the top 50th percentile decreased at 6 weeks and then returned to baseline by 12 weeks of CR. We hypothesized that nigrostriatal dopamine tissue content would be greater in the CR group and observed a modest increase only in substantia nigra with no group differences in striatum, nucleus accumbens, or ventral tegmental area. These results indicate that initiation of CR at middle age may reduce aging-related bradykinesia, and, furthermore, subjects with below average locomotor activity may increase baseline activity. Sustaining nigral dopamine neurotransmission may be one component of preserving locomotor capabilities during aging.

PMID: 26610387 [PubMed - as supplied by publisher]

Reproducibility of a continuous ramp lower body negative pressure protocol for simulating hemorrhage.

Fri, 11/27/2015 - 07:28
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Reproducibility of a continuous ramp lower body negative pressure protocol for simulating hemorrhage.

Physiol Rep. 2015 Nov;3(11)

Authors: Kay VL, Rickards CA

Abstract
Central hypovolemia elicited by application of lower body negative pressure (LBNP) has been used extensively to simulate hemorrhage in human subjects. Traditional LBNP protocols incorporate progressive steps in pressure held for specific time intervals. The aim of this study was to assess the reproducibility of applying continuous LBNP at a constant rate until presyncope to replicate actual bleeding. During two trials (≥4 weeks intervening), LBNP was applied at a rate of 3 mmHg/min in 18 healthy human subjects (12M; 6F) until the onset of presyncopal symptoms. Heart rate (HR), mean arterial pressure (MAP), stroke volume (SV), total peripheral resistance (TPR), mean middle and posterior cerebral artery velocities (MCAv, PCAv), and cerebral oxygen saturation (ScO2) were measured continuously. Time to presyncope (TTPS) and hemodynamic responses were compared between the two trials. TTPS (1649 ± 98 sec vs. 1690 ± 88 sec; P = 0.47 [t-test]; r = 0.77) and the subsequent magnitude of central hypovolemia (%Δ SV -54 ± 4% vs. -53 ± 4%; P = 0.55) were similar between trials. There were no statistically distinguishable differences at either baseline (P ≥ 0.17) or presyncope between trials for HR, MAP, TPR, mean MCAv, mean PCAv, or ScO2 (P ≥ 0.19). The rate of change from baseline to presyncope for all hemodynamic responses was also similar between trials (P ≥ 0.12). Continuous LBNP applied at a rate of 3 mmHg/min was reproducible in healthy human subjects, eliciting similar reductions in central blood volume and subsequent reflex hemodynamic responses.

PMID: 26607173 [PubMed - as supplied by publisher]

Cerebral small vessel disease and Alzheimer's disease.

Thu, 11/26/2015 - 07:29
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Cerebral small vessel disease and Alzheimer's disease.

Clin Interv Aging. 2015;10:1695-704

Authors: Cai Z, Wang C, He W, Tu H, Tang Z, Xiao M, Yan LJ

Abstract
Cerebral small vessel disease (CSVD) is a group of pathological processes with multifarious etiology and pathogenesis that are involved into the small arteries, arterioles, venules, and capillaries of the brain. CSVD mainly contains lacunar infarct or lacunar stroke, leukoaraiosis, Binswanger's disease, and cerebral microbleeds. CSVD is an important cerebral microvascular pathogenesis as it is the cause of 20% of strokes worldwide and the most common cause of cognitive impairment and dementia, including vascular dementia and Alzheimer's disease (AD). It has been well identified that CSVD contributes to the occurrence of AD. It seems that the treatment and prevention for cerebrovascular diseases with statins have such a role in the same function for AD. So far, there is no strong evidence-based medicine to support the idea, although increasing basic studies supported the fact that the treatment and prevention for cerebrovascular diseases will benefit AD. Furthermore, there is still lack of evidence in clinical application involved in specific drugs to benefit both AD and CSVD.

PMID: 26604717 [PubMed - in process]

Alternative Mitochondrial Electron Transfer for the Treatment of Neurodegenerative Diseases and Cancers: Methylene Blue Connects the Dots.

Thu, 11/26/2015 - 07:29
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Alternative Mitochondrial Electron Transfer for the Treatment of Neurodegenerative Diseases and Cancers: Methylene Blue Connects the Dots.

Prog Neurobiol. 2015 Nov 18;

Authors: Yang SH, Li W, Sumien N, Forster M, Simpkins JW, Liu R

Abstract
Brain has exceptional high requirement for energy metabolism with glucose as the exclusive energy source. Decrease of brain energy metabolism and glucose uptake has been found in patients of Alzheimer's, Parkinson's and other neurodegenerative diseases, providing a clear link between neurodegenerative disorders and energy metabolism. On the other hand, cancers, including glioblastoma, have increased glucose uptake and rely on aerobic glycolysis for energy metabolism. The switch of high efficient oxidative phosphorylation to low efficient aerobic glycolysis pathway (Warburg effect) provides macromolecule for biosynthesis and proliferation. Current research indicate that methylene blue, a century old drug, can receive electron from NADH in the presence of complex I and donates it to cytochrome C, providing an alternative electron transfer pathway. Methylene blue increases oxygen consumption, decrease glycolysis, and increases glucose uptake in vitro. Methylene blue enhances glucose uptake and regional cerebral blood flow in rats upon acute treatment. In addition, methylene blue provides protective effect in neuron and astrocyte against various insults in vitro and in rodent models of Alzheimer's, Parkinson's, and Huntington's disease. In glioblastoma cells, methylene blue reverses Warburg effect by enhancing mitochondrial oxidative phosphorylation, arrests glioma cell cycle at s-phase, and inhibits glioma cell proliferation. Accordingly, methylene blue activates AMP-activated protein kinase, inhibits downstream acetyl-coA carboxylase and cyclin-dependent kinases. In summary, there is accumulating evidence providing a proof of concept that enhancement of mitochondrial oxidative phosphorylation via alternative mitochondrial electron transfer may offer protective action against neurodegenerative diseases and inhibit cancers proliferation.

PMID: 26603930 [PubMed - as supplied by publisher]

Steady State and Time Resolved Fluorescence Studies of Azadioxatriangulenium (ADOTA) Fluorophore in Silica and PVA Thin Films.

Wed, 11/25/2015 - 10:53

Steady State and Time Resolved Fluorescence Studies of Azadioxatriangulenium (ADOTA) Fluorophore in Silica and PVA Thin Films.

Dyes Pigm. 2015 Jun 1;117:16-23

Authors: Chib R, Raut S, Shah S, Grobelna B, Akopova I, Rich R, Sørensen TJ, Laursen BW, Grajek H, Gryczynski Z, Gryczynski I

Abstract
A cationic azadioxatriangulenium (ADOTA) dye was entrapped in silica thin films obtained by the sol-gel process and in poly (vinyl) alcohol (PVA) thin films. Azadioxatriangulenium is a red emitting fluorophore with a long fluorescence lifetime of ~20 ns. The fluorescent properties of azadioxatriangulenium in silica thin films and PVA films were studied by means of steady-state and time resolved fluorescence techniques. We have found that the azadioxatriangulenium entrapped in silica thin film has a wider fluorescence lifetime distribution (Lorentzian distribution), lower fluorescence efficiencies, shorter lifetimes compared to Azadioxatriangulenium in a PVA film. The local environment of azadioxatriangulenium molecules in the silica thin film is rich with water and ethanol, which creates the possibility of forming excited state aggregates due to high concentration of dye within a small confined area. In contrast to the PVA matrices, the porous silica films allow restricted rotations of Azadioxatriangulenium molecules, which result in faster and complex fluorescence anisotropy decays suggesting energy migration among dye molecules.

PMID: 26594075 [PubMed - as supplied by publisher]

Effect of Quencher, Denaturants, Temperature and pH on the Fluorescent Properties of BSA Protected Gold Nanoclusters.

Wed, 11/25/2015 - 10:53

Effect of Quencher, Denaturants, Temperature and pH on the Fluorescent Properties of BSA Protected Gold Nanoclusters.

J Lumin. 2015 Dec 1;168:62-68

Authors: Chib R, Butler S, Raut S, Shah S, Borejdo J, Gryczynski Z, Gryczynski I

Abstract
In this paper, we have synthesized BSA protected gold nanoclusters (BSA Au nanocluster) and studied the effect of quencher, protein denaturant, pH and temperature on the fluorescence properties of the tryptophan molecule of the BSA Au nanocluster and native BSA. We have also studied their effect on the peak emission of BSA Au nanoclusters (650 nm). The phtophysical characterization of a newly developed fluorophore in different environments is absolutely necessary to futher develop their biomedical and analytical applications. It was observed from our experiments that the tryptophan in BSA Au nanoclusters is better shielded from the polar environment. Tryptophan in native BSA showed a red shift in its peak emission wavelength position. Tryptophan is a highly polarity sensitive dye and a minimal change in its microenvironment can be easily observed in its photophysical properties.

PMID: 26594061 [PubMed - as supplied by publisher]

Two-dimensional gel electrophoretic detection of protein carbonyls derivatized with biotin-hydrazide.

Mon, 11/23/2015 - 07:29

Two-dimensional gel electrophoretic detection of protein carbonyls derivatized with biotin-hydrazide.

J Chromatogr B Analyt Technol Biomed Life Sci. 2015 Nov 7;

Authors: Wu J, Luo X, Jing S, Yan LJ

Abstract
Protein carbonyls are protein oxidation products that are often used to measure the magnitude of protein oxidative damage induced by reactive oxygen or reactive nitrogen species. Protein carbonyls have been found to be elevated during aging and in age-related diseases such as stroke, diabetes, and neurodegenerative diseases. In the present article, we provide detailed protocols for detection of mitochondrial protein carbonyls labeled with biotin-hydrazide followed by 2-dimensional isoelectric focusing (IEF)/SDS-PAGE and Western blotting probed with horse-radish peroxidase-conjugated streptavidin. The presented procedures can also be modified for detection of carbonylation of non-mitochondrial proteins.

PMID: 26590475 [PubMed - as supplied by publisher]

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