Publications by authors named "Daniel A Brazeau"

30 Publications

  • Page 1 of 1

Sex-Dependent Changes in Vascular Function in Adult Rats Following Prenatal Exposure to Methamphetamine.

FASEB J 2022 May;36 Suppl 1

Department of Pharmaceutical Sciences, Marshall University School of Pharmacy, Huntington, WV.

Background: Prenatal exposure to central nervous system stimulants such as cocaine, nicotine, and caffeine alters cardiovascular function in adult offspring. Methamphetamine use during pregnancy is associated with negative consequences in the offspring. However, most studies of methamphetamine use during pregnancy have focused on behavioral and neurological outcomes. Relatively little is known regarding the impact of prenatal methamphetamine exposure on the adult cardiovascular system. This study examined the hypothesis that methamphetamine use during pregnancy alters contractile function of the vasculature in the adult offspring. We also investigated the role of perivascular adipose tissue (PVAT) in methamphetamine-induced changes in vascular function.

Methods: Pregnant female rats received daily injections of saline or methamphetamine (5 mg/kg) throughout gestation. Agonist-induced contraction and relaxation responses were measured in aortas of 5 month old offspring in the presence and absence of perivascular adipose tissue.

Results: Prenatal methamphetamine significantly attenuated acetylcholine-induced relaxation in male (but not female) aortas when PVAT remained intact. However, prenatal methamphetamine had no impact on acetylcholine-induced relaxation when PVAT was removed. Nitroprusside-induced relaxation was unaffected by prenatal methamphetamine. Prenatal exposure to methamphetamine had no impact on acetylcholine-induced relaxation in third order mesenteric arteries of male or female offspring regardless of the presence of PVAT. Angiotensin II-induced contractile responses were significantly potentiated in male (but not female) aortas regardless of the presence of PVAT. This effect was abolished by L-Nitro arginine methyl ester (L-NAME). Contractile responses to phenylephrine and serotonin were unaffected in both male and female aortas. Basal blood pressure in adult male and female offspring was also unaffected by prenatal exposure to methamphetamine.

Conclusions: Prenatal exposure to methamphetamine sex-dependently alters PVAT function in the aorta. Methamphetamine also enhances angiotensin II-induced contraction through a mechanism that involves suppression of nitric oxide signaling. These data provide evidence that methamphetamine use during pregnancy induces sex-dependent changes in the vasculature that may increase the risk of cardiovascular disease in adult offspring.
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http://dx.doi.org/10.1096/fasebj.2022.36.S1.R2396DOI Listing
May 2022

Trends in the Number of Authors and Institutions in Papers Published in AJPE 2015-2019.

Am J Pharm Educ 2022 Mar 4:8972. Epub 2022 Mar 4.

Marshall University, School of Pharmacy, Huntington, West Virginia

To investigate the number of authors and unique institutions per paper published in the (AJPE) in 2015-2019, and to examine the number of authors and unique institutions for papers that were nominated for the Rufus A. Lyman Award in the same period. Articles published in AJPE from 2015 through 2019 were reviewed. Data collected for each article included article type, number of authors, and number of institutions. Of the 811 articles published in AJPE during this period, the number of authors increased significantly from an average of 3.5 (1.8) to 4.5 (2.2). The number of unique institutions also increased significantly from 1.7 (1.1) to 2.4 (1.8). There is a trend toward a greater number of authors and unique institutions for the publications in one pharmacy education journal. Explanations for this trend may include pressure to publish, increased research complexity, and expanded interprofessional collaboration.
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http://dx.doi.org/10.5688/ajpe8972DOI Listing
March 2022

Prenatal Exposure to Methamphetamine Causes Vascular Dysfunction in Adult Male Rat Offspring.

Front Cardiovasc Med 2022 26;9:830983. Epub 2022 Jan 26.

Department of Pharmaceutical Sciences, Marshall University School of Pharmacy, Huntington, WV, United States.

Methamphetamine use during pregnancy can have negative consequences on the offspring. However, most studies investigating the impact of prenatal exposure to methamphetamine have focused on behavioral and neurological outcomes. Relatively little is known regarding the impact of prenatal methamphetamine on the adult cardiovascular system. This study investigated the impact of chronic fetal exposure to methamphetamine on vascular function in adult offspring. Pregnant female rats received daily saline or methamphetamine (5 mg/kg) injections starting on gestational day 1 and continuing until the pups were born. Vascular function was assessed in 5 month old offspring. Prenatal methamphetamine significantly decreased both the efficacy and potency of acetylcholine-induced relaxation in isolated male (but not female) aortas when perivascular adipose tissue (PVAT) remained intact. However, prenatal methamphetamine had no impact on acetylcholine-induced relaxation when PVAT was removed. Nitroprusside-induced relaxation of the aorta was unaffected by prenatal methamphetamine. Angiotensin II-induced contractile responses were significantly potentiated in male (but not female) aortas regardless of the presence of PVAT. This effect was reversed by L-nitro arginine methyl ester (L-NAME). Serotonin- and phenylephrine-induced contraction were unaffected by prenatal methamphetamine. Prenatal methamphetamine had no impact on acetylcholine-induced relaxation of third order mesenteric arteries and no effect on basal blood pressure. These data provide evidence that prenatal exposure to methamphetamine sex-dependently alters vasomotor function in the vasculature and may increase the risk of developing vascular disorders later in adult life.
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http://dx.doi.org/10.3389/fcvm.2022.830983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8826446PMC
January 2022

Race and sex associations with tacrolimus pharmacokinetics in stable kidney transplant recipients.

Pharmacotherapy 2022 02 1;42(2):94-105. Epub 2022 Feb 1.

Nephrology Division, Medicine, School of Medicine and Biomedical Sciences, Buffalo, New York, USA.

Study Objective: This study investigated race and sex differences in tacrolimus pharmacokinetics and pharmacodynamics in stable kidney transplant recipients.

Design And Setting: A cross-sectional, open-label, single center, 12-h pharmacokinetic-pharmacodynamic study was conducted. Tacrolimus pharmacokinetic parameters included area under the concentration-time curve (AUC ), AUC , 12-h troughs (C ), maximum concentrations (C ), oral clearance (Cl), with dose-normalized AUC , troughs, and C with standardized adverse effect scores. Statistical models were used to analyze end points with individual covariate-adjustment including clinical factors, genotypic variants CYP3A5*3, CYP3A5*6, CYP3A5*7(CYP3A5*3*6*7) metabolic composite, and ATP binding cassette gene subfamily B member 1 (ABCB1) polymorphisms.

Patients: 65 stable, female and male, Black and White kidney transplant recipients receiving tacrolimus and mycophenolic acid ≥6 months post-transplant were evaluated.

Measurements And Main Results: Black recipients exhibited higher tacrolimus AUC (Race: p = 0.005), lower AUC* (Race: p < 0.001; Race × Sex: p = 0.068), and higher Cl (Race: p < 0.001; Sex: p = 0.066). Greater cumulative (Sex: p < 0.001; Race × Sex: p = 0.014), neurologic (Sex: p = 0.021; Race × Sex: p = 0.005), and aesthetic (Sex: p = 0.002) adverse effects were found in females, with highest scores in Black women. In 84.8% of Black and 68.8% of White patients, the target AUC was achieved (p = 0.027). In 31.3% of White and 9.1% of Black recipients, AUC was <100 ng‧h/ml despite tacrolimus troughs in the target range (p = 0.027). The novel CYP3A5*3*6*7 metabolic composite was the significant covariate accounting for 15%-19% of tacrolimus variability in dose (p = 0.002); AUC * (p < 0.001), and Cl (p < 0.001).

Conclusions: Tacrolimus pharmacokinetics and adverse effects were different among stable kidney transplant recipient groups based upon race and sex with interpatient variability associated with the CYP3A5*3*6*7 metabolic composite. More cumulative, neurologic, and aesthetic adverse effects were noted among females. Tacrolimus regimens that consider race and sex may reduce adverse effects and enhance allograft outcomes by facilitating more patients to achieve the targeted AUC .
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http://dx.doi.org/10.1002/phar.2656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9020367PMC
February 2022

Methamphetamine-induced changes in myocardial gene transcription are sex-dependent.

BMC Genomics 2021 Apr 12;22(1):259. Epub 2021 Apr 12.

Department of Pharmaceutical Science, Marshall University School of Pharmacy, 1 John Marshall Drive, Huntington, WV, 25755, USA.

Background: Prior work demonstrated that female rats (but not their male littermates) exposed to methamphetamine become hypersensitive to myocardial ischemic injury. Importantly, this sex-dependent effect persists following 30 days of subsequent abstinence from the drug, suggesting that it may be mediated by long term changes in gene expression that are not rapidly reversed following discontinuation of methamphetamine use. The goal of the present study was to determine whether methamphetamine induces sex-dependent changes in myocardial gene expression and whether these changes persist following subsequent abstinence from methamphetamine.

Results: Methamphetamine induced changes in the myocardial transcriptome were significantly greater in female hearts than male hearts both in terms of the number of genes affected and the magnitude of the changes. The largest changes in female hearts involved genes that regulate the circadian clock (Dbp, Per3, Per2, BMal1, and Npas2) which are known to impact myocardial ischemic injury. These genes were unaffected by methamphetamine in male hearts. All changes in gene expression identified at day 11 returned to baseline by day 30.

Conclusions: These data demonstrate that female rats are more sensitive than males to methamphetamine-induced changes in the myocardial transcriptome and that methamphetamine does not induce changes in myocardial transcription that persist long term after exposure to the drug has been discontinued.
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http://dx.doi.org/10.1186/s12864-021-07561-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042975PMC
April 2021

Beyond Single Nucleotide Polymorphisms: Composite and Haplotype Associations to Tacrolimus Pharmacokinetics in Black and White Renal Transplant Recipients.

Front Genet 2020 11;11:889. Epub 2020 Aug 11.

Immunosuppressive Pharmacology Research Program, Translational Pharmacology Research Core, NYS Center of Excellence in Bioinformatics and Life Sciences, Buffalo, NY, United States.

Interpatient variability in tacrolimus pharmacokinetics is attributed to metabolism by cytochrome P-450 3A5 (CYP3A5) isoenzymes and membrane transport by P-glycoprotein. Interpatient pharmacokinetic variability has been associated with genotypic variants for both or . Tacrolimus pharmacokinetics was investigated in 65 stable Black and Caucasian post-renal transplant patients by assessing the effects of multiple alleles in both and A metabolic composite based upon the polymorphisms: (rs776746), (10264272), ), each independently responsible for loss of protein expression was used to classify patients as extensive, intermediate and poor metabolizers. In addition, the role of on tacrolimus pharmacokinetics was assessed using haplotype analysis encompassing the single nucleotide polymorphisms: > > > . Finally, a combined analysis using both and polymorphisms was developed to assess their inter-related influence on tacrolimus pharmacokinetics. Extensive metabolizers identified as homozygous wild type at all three loci were found in 7 Blacks and required twice the tacrolimus dose (5.6 ± 1.6 mg) compared to Poor metabolizers [2.5 ± 1.1 mg (P < 0.001)]; who were primarily Whites. These extensive metabolizers had 2-fold faster clearance ( < 0.001) with 50% lower AUC ( < 0.001) than Poor metabolizers. No differences in C were found due to therapeutic drug monitoring. The majority of blacks (81%) were classified as either Extensive or Intermediate Metabolizers requiring higher tacrolimus doses to accommodate the more rapid clearance. Blacks who were homozygous for one or more loss of function SNPS were associated with lower tacrolimus doses and slower clearance. These values are comparable to Whites, 82% of who were in the Poor metabolic composite group. The haplotype analysis detected significant associations of the wildtype haplotype to tacrolimus dose ( = 0.03), CL ( = 0.023), CL/LBW ( = 0.022), and AUC ( = 0.078). Finally, analysis combining and genotypes indicated that the presence of the 3435 T allele significantly reduced tacrolimus clearance for all three CPY3A5 metabolic composite groups. Genotypic associations of tacrolimus pharmacokinetics can be improved by using the novel composite haplotypes. Consideration of multiple alleles using metabolic composites and drug transporter ABCB1 haplotypes provides a more comprehensive appraisal of genetic factors contributing to interpatient variability in tacrolimus pharmacokinetics among Whites and Blacks.
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http://dx.doi.org/10.3389/fgene.2020.00889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433713PMC
August 2020

Influence of Exercise Time of Day on Salivary Melatonin Responses.

Int J Sports Physiol Perform 2019 Mar 5;14(3):351-353. Epub 2019 Feb 5.

Background: Sleep deprivation negatively affects cognition, pain, mood, metabolism, and immunity, which can reduce athletic performance. Melatonin facilitates sleepiness and may be affected by the proximity of exercise to sleep.

Purpose: To evaluate the influence of exercise time of day on salivary melatonin (s-melatonin) responses.

Methods: Twelve regularly exercising men (age 20.75 [0.62] y, height 1.75 [0.04] m, mass 73.63 [10.43] kg, and maximal oxygen consumption 57.72 [6.11] mL/kg/min) participated in a randomized, crossover design. Subjects completed 3 protocols-morning exercise (09:00 h), afternoon exercise (16:00 h), and no exercise (CON)-at least 5 d apart. Exercise sessions consisted of 30 min of steady-state running at 75% of maximal oxygen consumption. Saliva was collected via passive drool at 20:00, 22:00, and 03:00 h following all sessions.

Results: Repeated-measures analysis of variance revealed significant time (P = .001) and condition (P = .026) effects for melatonin. Levels of s-melatonin were significantly increased at 03:00 h compared with 20:00 and 22:00 h for all conditions. Post hoc analyses revealed that s-melatonin at 22:00 h was significantly higher after morning exercise (16.5 [7.5] pg/mL) compared with afternoon exercise (13.7 [6.1] pg/mL) sessions (P = .03), whereas neither exercise condition significantly differed from the control (P > .05).

Conclusions: It appears that exercising in the afternoon may blunt melatonin secretion compared with morning exercise. If sleep is an issue, morning exercise may be preferable to afternoon exercise.
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http://dx.doi.org/10.1123/ijspp.2018-0073DOI Listing
March 2019

Strong associations between plant genotypes and bacterial communities in a natural salt marsh.

Ecol Evol 2018 May 24;8(9):4721-4730. Epub 2018 Apr 24.

Department of Biomedical Sciences University of New England Biddeford Maine.

Although microbial communities have been shown to vary among plant genotypes in a number of experiments in terrestrial ecosystems, relatively little is known about this relationship under natural conditions and outside of select model systems. We reasoned that a salt marsh ecosystem, which is characterized by twice-daily flooding by tides, would serve as a particularly conservative test of the strength of plant-microbial associations, given the high degree of abiotic regulation of microbial community assembly resulting from alternating periods of inundation and exposure. Within a salt marsh in the northeastern United States, we characterized genotypes of the foundational plant using microsatellite markers, and bacterial metagenomes within marsh soil based on pyrosequencing. We found significant differences in bacterial community composition and diversity between bulk and rhizosphere soil, and that the structure of rhizosphere communities varied depending on the growth form of, and genetic variation within, the foundational plant . Our results indicate that there are strong plant-microbial associations within a natural salt marsh, thereby contributing to a growing body of evidence for a relationship between plant genotypes and microbial communities from terrestrial ecosystems and suggest that principles of community genetics apply to this wetland type.
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http://dx.doi.org/10.1002/ece3.4105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938472PMC
May 2018

Sequential Evolution of Vancomycin-Intermediate Resistance Alters Virulence in Staphylococcus aureus: Pharmacokinetic/Pharmacodynamic Targets for Vancomycin Exposure.

Antimicrob Agents Chemother 2015 Dec 28;60(3):1584-91. Epub 2015 Dec 28.

Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA New York State Center of Excellence in Life Sciences and Bioinformatics, University at Buffalo, Buffalo, New York, USA

Staphylococcus aureus possesses exceptional virulence and a remarkable ability to adapt in the face of antibiotic therapy. We examined the in vitro evolution of S. aureus in response to escalating vancomycin exposure by evaluating bacterial killing and the progression of resistance. A hollow-fiber infection model was utilized to simulate human doses of vancomycin increasing from 0.5 to 4 g every 12 h (q12h) versus a high inoculum (10(8) CFU/ml) of methicillin-resistant S. aureus (MRSA) USA300 and USA400. Host-pathogen interactions using Galleria mellonella and accessory gene regulator (agr) expression were studied in serially obtained isolates. In both USA300 and USA400 MRSA isolates, vancomycin exposure up to 2 g q12h resulted in persistence and regrowth, whereas 4 g administered q12h achieved sustained killing against both strains. As vancomycin exposure increased from 0.5 to 2 g q12h, the bacterial population shifted toward vancomycin-intermediate resistance, and collateral increases in the MICs of daptomycin and televancin were observed over 10 days. Guideline-recommended exposure of a ratio of the area under the concentration-time curve for the free, unbound fraction of the drug to the MIC (fAUC/MIC ratio) of 200 displayed a 0.344-log bacterial reduction in area, whereas fAUC/MICs of 371 and 554 were needed to achieve 1.00- and 2.00-log reductions in area, respectively. The stepwise increase in resistance paralleled a decrease in G. mellonella mortality (P = 0.021) and a gradual decline of RNAIII expression over 10 days. Currently recommended doses of vancomycin resulted in amplification of resistance and collateral damage to other antibiotics. Decreases in agr expression and virulence during therapy may be an adaptive mechanism of S. aureus persistence.
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http://dx.doi.org/10.1128/AAC.02657-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4776009PMC
December 2015

Genetic structure in the coral, Montastraea cavernosa: assessing genetic differentiation among and within Mesophotic reefs.

PLoS One 2013 29;8(5):e65845. Epub 2013 May 29.

Department of Pharmaceutical Sciences, University of New England, Portland, Maine, USA.

Mesophotic coral reefs (30-150 m) have recently received increased attention as a potential source of larvae (e.g., the refugia hypothesis) to repopulate a select subset of the shallow water (<30 m) coral fauna. To test the refugia hypothesis we used highly polymorphic Amplified Fragment Length Polymorphism (AFLP) markers as a means to assess small-scale genetic heterogeneity between geographic locations and across depth clines in the Caribbean coral, Montastraea cavernosa. Zooxanthellae-free DNA extracts of coral samples (N = 105) were analyzed from four depths, shallow (3-10 m), medium (15-25 m), deep (30-50 m) and very deep (60-90 m) from Little Cayman Island (LCI), Lee Stocking Island (LSI), Bahamas and San Salvador (SS), Bahamas which range in distance from 170 to 1,600 km apart. Using AMOVA analysis there were significant differences in ΦST values in pair wise comparisons between LCI and LSI. Among depths at LCI, there was significant genetic differentiation between shallow and medium versus deep and very deep depths in contrast there were no significant differences in ΦST values among depths at LSI. The assignment program AFLPOP, however, correctly assigned 95.7% of the LCI and LSI samples to the depths from which they were collected, differentiating among populations as little as 10 to 20 m in depth from one another. Discriminant function analysis of the data showed significant differentiation among samples when categorized by collection site as well as collection depth. FST outlier analyses identified 2 loci under positive selection and 3 under balancing selection at LCI. At LSI 2 loci were identified, both showing balancing selection. This data shows that adult populations of M. cavernosa separated by depths of tens of meters exhibits significant genetic structure, indicative of low population connectivity among and within sites and are not supplying successful recruits to adjacent coral reefs less than 30 m in depth.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0065845PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3666989PMC
January 2014

Genetic connectivity in scleractinian corals across the Northern Gulf of Mexico: oil/gas platforms, and relationship to the Flower Garden Banks.

PLoS One 2012 30;7(4):e30144. Epub 2012 Apr 30.

Louisiana Universities Marine Consortium, Chauvin, Louisiana, United States of America.

The 3,000 oil/gas structures currently deployed in the northern Gulf of Mexico (GOM) provide hard substratum for marine organisms in a region where such has been rare since the Holocene. The major exception to this are the Flower Garden Banks (FGB). Corals are known to have colonized oil/gas platforms around the FGB, facilitating biogeographic expansion. We ask the question, what are the patterns of genetic affinity in these coral populations. We sampled coral tissue from populations of two species occurring on oil and gas platforms: Madracis decactis (hermatype) and Tubastraea coccinea (invasive ahermatype). We sampled 28 platforms along four transects from 20 km offshore to the continental shelf edge off 1) Matagorda Island, TX; 2) Lake Sabine, TX; 3) Terrebonne Bay, LA; and 4) Mobile, AL. The entire population of M. decactis was sampled between depths of 5 m and 37 m. T. coccinea populations were sub-sampled. Genetic variation was assessed using the PCR-based Amplified Fragment Length Polymorphisms (AFLPs). Data were analyzed via AFLPOP and STRUCTURE. Genetic connectivity among M. decactis platform populations was highest near the FGB and decreased to the east. Connectivity increased again in the eastern sector, indicating isolation between the populations from different sides of the Mississippi River (Transects 3 and 4). A point-drop in genetic affinity (relatedness) at the shelf edge south of Terrebonne Bay, LA indicated a population differing from all others in the northern GOM. Genetic affinities among T. coccinea were highest in the west and decreased to the east. Very low genetic affinities off Mobile, AL indicated a dramatic difference between those populations and those west of the Mississippi River, apparently a formidable barrier to larval dispersal.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0030144PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3340370PMC
September 2012

Front-loaded linezolid regimens result in increased killing and suppression of the accessory gene regulator system of Staphylococcus aureus.

Antimicrob Agents Chemother 2012 Jul 23;56(7):3712-9. Epub 2012 Apr 23.

Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA.

Front loading is a strategy used to optimize the pharmacodynamic profile of an antibiotic through the administration of high doses early in therapy for a short duration. Our aims were to evaluate the impact of front loading of linezolid regimens on bacterial killing and suppression of resistance and on RNAIII, the effector molecule of the accessory gene regulator system (encoded by agr) in methicillin-resistant Staphylococcus aureus (MRSA). Time-killing experiments over 48 h were utilized for linezolid against four strains of MRSA: USA100, USA300, USA400, and ATCC 29213. A hollow-fiber infection model simulated traditional and front-loaded human therapeutic regimens of linezolid versus USA300 at 10(6) CFU/ml over 240 h. Over 48 h in time-kill experiments, linezolid displayed bacteriostatic activity, with reductions of >1 log(10) CFU/ml for all strains. Front-loaded regimens that were administered over 5 days, 1,200 mg every 12 h (q12h) (total, 10 doses) and 2,400 mg q12h (total, 10 doses) followed by 300 mg q12h thereafter, resulted in sustained bactericidal activity, with reductions of the area under the CFU curve of -6.15 and -6.03, respectively, reaching undetectable limits at the 10-day study endpoint. All regimens displayed a reduction in RNAIII relative expression at 24 h and 240 h compared with that of the growth control. Monte Carlo simulations predicted a <1.27× increase in the fractional decreases in platelets for all front-loaded regimens versus the 600 mg q12h regimen, except for the highest-dose front-loaded regimen. Front-loading strategies for linezolid are promising and may be of utility in severe MRSA infections, where early aggressive therapy is necessary.
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http://dx.doi.org/10.1128/AAC.05453-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3393439PMC
July 2012

Effects of methylphenidate on fatigue and depression: a randomized, double-blind, placebo-controlled trial.

J Pain Symptom Manage 2012 Jan;43(1):68-77

The Center for Hospice & Palliative Care, Buffalo, New York, USA.

Context: Fatigue is highly prevalent in populations with advanced illness and is often associated with depressed mood. The role of psychostimulant therapy in the treatment of these conditions remains ill defined.

Objectives: To evaluate the response of fatigue and depression in patients with advanced illness to titrated doses of methylphenidate (MP) as compared with placebo.

Methods: In a randomized, double-blind, placebo-controlled trial, 30 hospice patients, both inpatients and outpatients, who had fatigue scores of at least four on a scale of zero to 10 (0=no fatigue and 10=worst fatigue), were randomly assigned to receive either 5mg of MP at 8 am and 1 pm or placebo. Doses of MP were titrated every three days according to response and adverse effects. Home care patients were monitored daily by telephone and visited by a research nurse on Study Days 0 (baseline), 3, 7, and 14. Fatigue was assessed using the Piper Fatigue Scale as the primary outcome measure and validated by the Visual Analogue Scale for Fatigue and the Edmonton Symptom Assessment Scale (ESAS) fatigue score. Subjects in inpatient facilities were interviewed or assessed by staff on an identical schedule. Depressive symptoms were assessed by the Beck Depression Inventory-II, Center for Epidemiologic Studies Depression Scale, and the ESAS depression score. Primary statistical analysis was conducted using repeated-measures multivariate analysis of the variance.

Results: Both MP- and placebo-treated groups had similar measures of fatigue at baseline. Patients taking MP were found to have significantly lower fatigue scores (Piper Fatigue Scale, Visual Analogue Scale for Fatigue, and ESAS) at Day 14 compared with baseline. The improvement in fatigue with MP treatment was dose-dependent; the mean average effective dose was 10mg on Day 3 and 20mg on Day 14 (dose range of 10-40 mg). Placebo-treated individuals showed no significant improvement in fatigue. For patients with clinically significant depression on Day 0, treatment with MP was associated with a significant reduction in all test indices for depressed mood. For the placebo group, the changes in measures of depression were less than observed in the treatment group but were inconsistent between assessment tools. No significant toxicities were observed.

Conclusion: MP reduced symptoms of fatigue and depression when compared with placebo. The effect of MP on fatigue was dose-dependent and sustained over the duration of the study.
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http://dx.doi.org/10.1016/j.jpainsymman.2011.03.026DOI Listing
January 2012

Nitroglycerin alters matrix remodeling proteins in THP-1 human macrophages and plasma metalloproteinase activity in rats.

Nitric Oxide 2011 Mar 13;24(2):66-76. Epub 2010 Dec 13.

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14260, USA.

Several studies suggested that long-term nitrate therapy may produce negative outcomes in patient mortality and morbidity. A possible mechanism may involve nitrate-mediated activation of various extracellular matrix (ECM) proteases, particularly matrix metalloproteinase-9 (MMP-9), and adhesion molecules in human macrophages, leading to the destabilization of atherosclerotic plaques. We examined the gene and protein regulating effects on THP-1 human macrophages by repeated exposure to therapeutically relevant concentrations of nitroglycerin (NTG) and possible involvement of nuclear factor (NF)-κB signaling mechanism in mediating some of these observed effects. THP-1 human macrophages repeatedly exposed to NTG (at 10 nM, added on days 1, 4 and 7) exhibited extensive alterations in the expression of multiple genes encoding ECM proteases and adhesion molecules. These effects were dissimilar to those produced by a direct nitric oxide donor, diethylenetriamine NONOate. NTG exposure significantly up-regulated NF-κB DNA nuclear binding activity and MMP-9 protein expression, and reduced tissue inhibitor of metalloproteinase-1 (TIMP-1) expression; these effects were abrogated in the presence of the NF-κB inhibitor parthenolide (a chemical inhibitor derived from the feverfew plant). Further, we examined whether our in vitro findings (an elevated MMP-9/TIMP-1 ratio and gelatinase activity) can be translated to in vivo effects, in a rat model. Sprague-Dawley rats exposed continuously to NTG subcutaneously for 8 days via mini-osmotic pumps showed significant induction of plasma MMP-9 dimer concentrations and the expression of a complex of MMP-9 with lipocalin-2 or neutrophil gelatinase associated lipocalin (NGAL). Plasma gelatinase activity was significantly increased by NTG over the entire study period, attaining peak elevation at day 6. Plasma TIMP-1 protein was down-regulated significantly by day 2 and days 4-7 in the NTG-treated rats. Pharmacokinetic monitoring of NTG and its dinitrate metabolites indicated that concentrations were well within therapeutic levels observed in humans. Our studies indicate that clinically relevant concentrations of NTG not only altered ECM matrix by changing the expression of multiple genes that govern cellular integrity, affecting cellular MMP-9/TIMP-1 balance in THP-1 human macrophages possibly via NF-κB activation, but also led to systemic changes in MMP-9/TIMP-1 expression and gelatinase activity in rats. These effects may contribute to extracellular matrix degradation and possible atherosclerotic plaque destabilization.
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http://dx.doi.org/10.1016/j.niox.2010.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3039075PMC
March 2011

Dietary phenethyl isothiocyanate alters gene expression in human breast cancer cells.

Evid Based Complement Alternat Med 2011 28;2011. Epub 2010 Sep 28.

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Amherst, NY 14260, USA.

Phenethyl isothiocyanate (PEITC), a component in cruciferous vegetables, can block chemical carcinogenesis in animal models. Our objective was to determine the effect of treatment with PEITC on gene expression changes in MCF-7 human breast cancer cells in order to evaluate potential mechanisms involved in its chemopreventive effects. MCF-7 cells were treated for 48 hours with either PEITC (3 μM) or the vehicle. Total RNA was extracted from cell membrane preparations, and labeled cDNA's representing the mRNA pool were reverse-transcribed directly from total RNA isolated for use in the microarray hybridizations. Two specific human GE Array Kits (Superarray Inc.) that both contain 23 marker genes, related to signal transduction pathways or cancer/tumor suppression, plus 2 housekeeping genes (β-actin and GAPDH), were utilized. Arrays from treated and control cells (n = 4 per group) were evaluated using a Student's t-test. Gene expression was significantly induced for tumor protein p53 (p53), cyclin-dependent kinase inhibitor 1C (p57 Kip2), breast cancer Type 2 early onset (BRCA2), cAMP responsive element binding protein 2 (ATF-2), interleukin 2 (IL-2), heat shock 27 KD protein (hsp27), and CYP19 (aromatase). Induction of p57 Kip2, p53, BRCA2, IL-2, and ATF-2 would be expected to decrease cellular proliferation and increase tumor suppression and/or apoptosis. PEITC treatment produced significant alterations in some genes involved in tumor suppression and cellular proliferation/apoptosis that may be important in explaining the chemopreventive effects of PEITC.
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http://dx.doi.org/10.1155/2011/462525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2952307PMC
July 2011

Environmental symbiont acquisition may not be the solution to warming seas for reef-building corals.

PLoS One 2010 Oct 7;5(10):e13258. Epub 2010 Oct 7.

Graduate Program in Evolution, Ecology and Behavior, Department of Geology, University at Buffalo, Buffalo, New York, United States of America.

Background: Coral reefs worldwide are in decline. Much of the mortality can be attributed to coral bleaching (loss of the coral's intracellular photosynthetic algal symbiont) associated with global warming. How corals will respond to increasing oceanic temperatures has been an area of extensive study and debate. Recovery after a bleaching event is dependent on regaining symbionts, but the source of repopulating symbionts is poorly understood. Possibilities include recovery from the proliferation of endogenous symbionts or recovery by uptake of exogenous stress-tolerant symbionts.

Methodology/principal Findings: To test one of these possibilities, the ability of corals to acquire exogenous symbionts, bleached colonies of Porites divaricata were exposed to symbiont types not normally found within this coral and symbiont acquisition was monitored. After three weeks exposure to exogenous symbionts, these novel symbionts were detected in some of the recovering corals, providing the first experimental evidence that scleractinian corals are capable of temporarily acquiring symbionts from the water column after bleaching. However, the acquisition was transient, indicating that the new symbioses were unstable. Only those symbiont types present before bleaching were stable upon recovery, demonstrating that recovery was from the resident in situ symbiont populations.

Conclusions/significance: These findings suggest that some corals do not have the ability to adjust to climate warming by acquiring and maintaining exogenous, more stress-tolerant symbionts. This has serious ramifications for the success of coral reefs and surrounding ecosystems and suggests that unless actions are taken to reverse it, climate change will lead to decreases in biodiversity and a loss of coral reefs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0013258PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2951366PMC
October 2010

Broad regulation of matrix and adhesion molecules in THP-1 human macrophages by nitroglycerin.

Nitric Oxide 2010 Jan 15;22(1):11-7. Epub 2009 Oct 15.

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14260-1200, USA.

Although nitroglycerin (NTG) is effective for the acute relief in coronary ischemic diseases, its long-term benefits in mortality and morbidity have been questioned. The possibility has been raised that NTG may increase the activity of matrix metalloproteinases (MMP), which could lead to disruption and dislodging of atherosclerotic plaques. This study examined the broad effects of acute NTG exposure on the expression and activity of genes encoding MMP-9, as well as an array of ECM and adhesion molecules in THP-1 human macrophages. Gene array studies identified that while NTG exposure (100microM, 48h) did not significantly increase MMP-9 gene expression, genes encoding testican-1, integrin alpha-1, thrombospondin-3, fibronectin-1 and MMP-26 were significantly down-regulated. On the other hand, genes encoding catenin beta-1 and vascular cell-adhesion molecule-1 were up-regulated. Real-time PCR studies confirmed significant down-regulation of testican-1 gene expression, but its protein expression was not significantly altered. NTG exposure, caused a significant increase in total MMP-9 protein expression (1.96-fold) and active MMP-9 (3.7-fold) concentrations. Recombinant MMP-9 was significantly activated by NTG and its dinitrate metabolites, indicating post-translation modification of this protein by organic nitrates. These results indicate that NTG exposure could broadly affect the gene expression and activity of proteases that govern the ECM cascade, thereby potentially altering atherosclerotic plaque stability.
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http://dx.doi.org/10.1016/j.niox.2009.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2818296PMC
January 2010

Relationship between student leadership activities and prepharmacy years in college.

Am J Pharm Educ 2008 Dec;72(6):149

School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Amherst, NY 14260, USA.

Objective: To determine whether a relationship exists between the number of years of college completed before entering pharmacy school and students' leadership involvement.

Methods: All pharmacy students from 2004-2007 were classified based upon their educational level at time of matriculation: Early Assurance Program (EA); 2 years of college, but not EA (2Y); 3 or more years of college but no degree (3Y+); and bachelor's degree or higher (BD). In terms of leadership positions, students were classified as holding any office, total number of offices, and Phi Lambda Sigma (PLS) membership.

Results: Students who entered the pharmacy program as EA students held 27.1% or 71 offices compared to 31.9% or 45 for 2Y, 26.8% or 39 for 3Y+ and 30.2% or 80 for BD students. Students selected for PLS were 12.1% for EA, 15.3% for 2Y, 16.1% for 3Y+ and 13.5% for BD. There was no significant relationship between prepharmacy education and leadership measurements.

Conclusions: Although no relationship was found between pharmacy students' involvement in leadership activities and number of prepharmacy years of education, the importance of predictive factors and approaches to evaluate students' leadership activities and involvement merits further research.
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http://dx.doi.org/10.5688/aj7206149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2661176PMC
December 2008

Comparison of the effects of phenethyl isothiocyanate and sulforaphane on gene expression in breast cancer and normal mammary epithelial cells.

Exp Biol Med (Maywood) 2009 Mar 14;234(3):287-95. Epub 2009 Jan 14.

Department of Pharmaceutical Sciences, 517 Hochstetter Hall, University at Buffalo, State University of New York, Amherst, NY 14260-1200, USA.

Phenethyl isothiocyanate (PEITC) and sulforaphane (SF) exhibit tumor preventive activity in lung, prostate, breast and colon cancers. Our objective was to examine the effect of these two isothiocyanates on estrogen receptor-related genes, and genes related to apoptosis and cell cycle in the estrogen-dependent breast cancer cell line MCF7 and in normal human epithelial breast (HME) cells. We treated cells with 0.3 microM or 3.0 microM concentrations of PEITC or SF. In HME cells, gene expression was significantly altered for 23 genes by PEITC at a concentration of 0.3 microM and 4 genes at 3.0 microM. SF altered the expression of 16 genes at a concentration of 0.3 microM and 2 genes at 3.0 microM. In HME cells, genes altered by both PEITC and SF exhibited changes in gene expression that were similar in extent as well as direction of change. In MCF-7 cells, PEITC did not produce any significant changes in the gene expression at both treatment levels. SF produced significant changes in 7 genes, but only at the higher treatment level of 3.0 microM. Normal mammary cells exhibited more changes in the expression of estrogen receptor related genes than did breast cancer cells, and significantly these changes occurred predominantly at the low concentration of 0.3 microM, a concentration achievable by dietary input of isothiocyanates. Novel findings were the upregulation of the pro-apoptotic gene BAD and estrogen receptor beta gene in normal human mammary cells. These gene alterations observed, along with upregulation of tumor suppressors p21 and p27, may provide a protective effect to mammary cells against breast cancer.
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http://dx.doi.org/10.3181/0808-RM-241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3698577PMC
March 2009

Estrogen effects on skeletal muscle insulin-like growth factor 1 and myostatin in ovariectomized rats.

Exp Biol Med (Maywood) 2007 Nov;232(10):1314-25

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, 517 Hochstetter Hall, North Campus, University at Buffalo, Amherst, New York 14260, USA.

Previous work showed that estrogen replacement attenuates muscle growth in immature rats. The present study examined muscle insulin-like growth factor-1 (IGF-1) and myostatin expression to determine whether these growth regulators might be involved in mediating estrogen's effects on muscle growth. IGF-1 and myostatin message and protein expression in selected skeletal muscles from 7-week-old sham-ovariectomized (SHAM) and ovariectomized rats that received continuous estrogen (OVX/E2) or solvent vehicle (OVX/CO) from an implant for 1 week or 5 weeks was measured. In the 1-week study, ovariectomy increased IGF-1 mRNA expression in fast extensor digitorum longus and gastrocnemius muscles; the increase was reversed by estrogen replacement. A similar trend was observed in the slow soleus muscle, although the change was not statistically significant. In contrast to mRNA, muscle IGF-1 protein expression was not different between SHAM and OVX/ CO animals in the 1-week study. One week of estrogen replacement significantly decreased IGF-1 protein level in all muscles examined. Myostatin mRNA expression was not different among the 1-week treatment groups. One week of estrogen replacement significantly increased myostatin protein in the slow soleus muscle but not the fast extensor digitorum longus and gastrocnemius muscles. There was no treatment effect on IGF-1 and myostatin expression in the 5-week study; this finding suggested a transient estrogen effect or upregulation of a compensatory mechanism to counteract the estrogen effect observed at the earlier time point. This investigation is the first to explore ovariectomy and estrogen effects on skeletal muscle IGF-1 and myostatin expression. Results suggest that reduced levels of muscle IGF-1 protein may mediate estrogen's effect on growth in immature, ovariectomized rats. Increased levels of muscle myostatin protein may also have a role in mediating estrogen's effects on growth in slow but not fast skeletal muscle.
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http://dx.doi.org/10.3181/0704-RM-92DOI Listing
November 2007

Prepharmacy years in college and academic performance in a professional program.

Am J Pharm Educ 2007 Aug;71(4):69

School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, USA.

Objective: This study investigated whether there was a significant difference in the cumulative grade point average (GPA) of individual students at the end of their first 3 professional years in the doctor of pharmacy curriculum as a function of previous years in college.

Methods: The cumulative GPA for the first- through third-professional years was calculated for the 2004-2007 graduating classes. Previous college education was classified as 2 years, 3 or more years without a bachelor's degree, and bachelor's degree or higher. Students with 2 years of prepharmacy education were classified as early assurance (EA) versus non-early assurance. Specifically, non-early assurance students were those who transferred in after 2 years but did not participate in the early assurance program. Statistical differences in the cumulative GPA were calculated using MANOVA with repeated measures followed by a LSD Post-Hoc test.

Results: Students with a bachelor's degree performed better academically, especially in the first professional year of the program compared to those with other levels of education including those who entered through our EA program. There was a consistent decrease in cumulative GPA during the second-professional year, but no additional change in the third-professional year.

Conclusions: Students who obtain a bachelor's degree perform better academically presumably because of previous college experiences.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959209PMC
http://dx.doi.org/10.5688/aj710469DOI Listing
August 2007

Effects of flavonoids genistein and biochanin a on gene expression and their metabolism in human mammary cells.

Nutr Cancer 2007 ;57(1):48-58

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Amherst, New York 14260, USA.

Genistein (GEN) and biochanin A (BCA), dietary isoflavones, possess breast cancer-preventive properties. Our objective was to examine the effect of physiologically relevant concentrations of BCA and GEN on gene expression in normal (HMEC), immortalized but nontumorigenic (MCF12A), and tumorigenic (MCF7) mammary cells and to determine whether the differences in gene expression are related to differences in metabolism in the three types of mammary cells. Using cDNA arrays, we compared the gene expression after a 48-h incubation with 1 microM BCA, GEN, or vehicle. Treatment with GEN or BCA produced the greatest number of significant changes in HMEC compared with MCF12A or MCF7 cells. Unlike GEN, effects of BCA on gene expression were mostly beneficial, involving induction of tumor suppressor genes. Different extents of metabolism were observed in the three mammary cell types; however, GEN concentrations were very low following either GEN or BCA administration in all of the three cell types. Because there were only very low concentrations of GEN, compared with BCA concentrations, in HMEC and MCF12A cells treated with BCA and different gene expression changes were found after BCA and GEN treatment, these findings suggest that BCA has distinct effects compared with GEN. The results suggest that BCA may represent a better breast cancer-preventive agent than GEN.
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http://dx.doi.org/10.1080/01635580701268196DOI Listing
July 2007

Effects of the flavonoid biochanin A on gene expression in primary human hepatocytes and human intestinal cells.

Mol Nutr Food Res 2007 Mar;51(3):317-23

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Amherst, NY 14260, USA.

Biochanin A (BCA), a phytoestrogen present in plant food and herbal products, has been reported to have cancer-preventive effects that may be mediated, in part, through effects on carcinogen metabolism. Our objective was to examine the effect of BCA on gene expression for drug-metabolizing enzymes and transporters in human hepatocytes. Cells were exposed to 20 muM of BCA for 5 days. Gene expression was assessed by a 96-gene human drug metabolism enzyme microarray. There were seven genes that were significantly up-regulated, namely cytochrome P-450 (CYP) 2A6, CYP2B6, CYP2C9, CYP2F1, multidrug resistance gene (MDR1), thromboxane A synthase 1 (TBXAS1), and SULT1A2 (sulfotransferase). Up-regulation of MDR1, which encodes for P-glycoprotein, was confirmed using real-time RT-PCR and Western analysis in hepatocytes as well as in human colon adenocarcinoma cell line (LS-180) and the induction was dose-dependent. BCA treatment up-regulated genes mainly in the CYP2 family. This induction can influence the metabolism of xenobiotics, producing effects of pharmacological and toxicological importance.
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http://dx.doi.org/10.1002/mnfr.200600156DOI Listing
March 2007

A required course in human genomics, pharmacogenomics, and bioinformatics.

Am J Pharm Educ 2006 Dec;70(6):125

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, NY, USA.

Objectives: To provide students with an understanding of the principles and applications of human genetics and genomics in drug therapy optimization, patient care, and counseling.

Design: A 2-credit hour course entitled Principles of the Human Genome, Pharmacogenomics, and Bioinformatics was offered to third-professional year PharmD students. Written examinations, in-class exercises, and a written paper evaluating the current literature were used to evaluate student learning.

Assessment: Student course ratings on the pedagogical format of the course and the relevance of course material to professional practice have improved significantly since first implementation in 2002.

Conclusion: This course provided pharmacy students with an understanding of pharmacogenetics ranging from genetic principles and the inheritance of complex traits to specific examples of pharmacogenomics in drug therapy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1803705PMC
http://dx.doi.org/10.5688/aj7006125DOI Listing
December 2006

Nicotinamide prevents apoptosis in human cortical neuronal cells.

Toxicol Mech Methods 2006 ;16(4):173-80

College of Pharmacy, South Dakota State University, Brookings, South Dakota, USA.

In previous studies, the free radical generating toxin tertiary butylhydroperoxide (t-BuOOH) was found to induce significant cell death in human cortical neuronal cells (HCN2 cells). Pretreatment with the poly (ADP-ribose) polymerase (PARP) inhibitor nicotinamide was able to prevent HCN2 cell death. In this study it is observed that apoptosis is induced following the addition of t-BuOOH at 6 h as indicated by TUNEL-positive cells. When nicotinamide is added prior to t-BuOOH, it is able to prevent neuronal cell death and inhibit apoptosis. DNA microarray studies demonstrate that t-BuOOH administration causes an upregulation of proapoptotic genes like ICH-2 and BimL. On the other hand, nicotinamide-pretreated neurons have higher expression levels of inhibitors of apoptosis (IAP) genes. Therefore, it appears that one mechanism by which nicotinamide acts as neuroprotective agents is by elevating the gene expression levels of IAPs. Moreover, there is an upregulation of the glyceraldehydes-3-phosphate dehydrogenase gene in nicotinamide-pretreated HCN2 cells. Nicotinamide-pretreated cells also had higher expression levels of putative "death domain" genes like p75TNFR, TRAIL2, TNFR1, and HVEM-L. Thus, nicotinamide can regulate multiple apoptotic genes with seemingly opposite roles and through its action on these various genes prevent apoptosis of neuronal cells.
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http://dx.doi.org/10.1080/15376520500194726DOI Listing
October 2012

Determination of nitric oxide-donor effects on tissue gene expression in vivo using low-density gene arrays.

Methods Enzymol 2005 ;396:387-95

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14260-1200, USA.

Gene array technology has been used to examine gene expression changes following drug treatments, including administration of nitric oxide (NO) donors. High-density arrays represent a powerful and popular method to analyze a large number of genes simultaneously. On the other hand, low-density arrays, available commercially at a lower cost, allow for the use of gene-specific primers, which reduces the risk of cross-hybridization among genes with similar sequence. For certain experiments in which the hypothesis is focused on a selected set of genes, use of low-density arrays might be more productive and cost-effective. Here, we describe our experience using low-density arrays to examine the effect of exposure to the NO-donor isobutyl nitrite on the expression of 23 cancer- and angiogenesis-related genes in mouse tissues. Detailed descriptions of data capture procedures, statistical tests, and confirmation studies using real-time quantitative (RTQ) reverse transcription polymerase chain reaction (RT-PCR) are presented. Three simple statistical methods, namely Student's t test, significant analysis of microarrays (SAM), and permutation adjusted t statistics (PATS), were applied on our gene array data, and their utilities were compared. All three methods yielded concordant results for the most significant genes, namely vascular endothelial growth factor (VEGF), VEGF receptor 3, Smad5, and Smad7. RT-PCR confirmed VEGF upregulation as observed via gene arrays. PATS appeared to be more robust than SAM in handling our small gene array data set. This statistical method, therefore, appears more suited for analyzing low-density gene array data. We conclude that low-density gene array is a useful screening method that can be performed with lower cost and less cumbersome data treatment.
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http://dx.doi.org/10.1016/S0076-6879(05)96033-3DOI Listing
January 2006

Effects of repeated in vivo inhalant nitrite exposure on gene expression in mouse liver and lungs.

Nitric Oxide 2006 Jun 8;14(4):279-89. Epub 2005 Nov 8.

Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA.

Exposure to inhalant organic nitrites (drugs of abuse commonly known as "poppers") has been reported to enhance tumor growth in mice, but the mechanism is not fully defined. This study examined the effect of repeated in vivo nitrite exposures on gene expression in the mouse liver and lungs using a gene array panel of 94 cancer- and angiogenesis-related genes. Using 2-fold change as a threshold criterion, repeated nitrite exposure was found to alter the expression of 65 and 23 genes in the liver and lungs, respectively. Six genes were significantly upregulated (p
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http://dx.doi.org/10.1016/j.niox.2005.09.010DOI Listing
June 2006

Combining genome-wide and targeted gene expression profiling in drug discovery: microarrays and real-time PCR.

Authors:
Daniel A Brazeau

Drug Discov Today 2004 Oct;9(19):838-45

Pharmaceutical Genetics Laboratory, Department of Pharmaceutical Sciences, University at Buffalo State, University of New York, Buffalo, NY, USA.

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http://dx.doi.org/10.1016/S1359-6446(04)03231-3DOI Listing
October 2004

Inhalant nitrite exposure alters mouse hepatic angiogenic gene expression.

Biochem Biophys Res Commun 2003 Oct;310(2):439-45

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA.

Inhalant nitrites are drugs of abuse that have been shown to enhance tumor growth rate in mice and are epidemiologically linked to an increased risk of Kaposi's sarcoma. Because nitrites produce nitric oxide, we hypothesized that their toxicological effects might be partly mediated via regulation of angiogenic factors such as vascular endothelial growth factor (VEGF). Preliminary studies showed that isobutyl nitrite (ISBN) incubation stimulated VEGF protein expression in J774 macrophage cells. C57BL/6 mice exposed to ISBN in air exhibited significant up-regulation of VEGF protein and mRNA in the liver, but not in the lung. Liver mRNA expression of VEGF receptor 2 (VEGFR-2), VEGFR-3, Smad5, and Smad7 was also significantly altered. These results demonstrate that in vivo exposure to an inhalant nitrite results in altered tissue expression of VEGF and its receptors, suggesting that some of its toxicological effects may be mediated partly through a mechanism involving angiogenesis.
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http://dx.doi.org/10.1016/j.bbrc.2003.09.041DOI Listing
October 2003
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