Gene/Protein Disease Symptom Drug Enzyme Compound
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Many years of behavioral and neurobiology studies have demonstrated broad physiological and pharmacological effects of nicotine on the central nervous system (CNS). However, the gene expression profiles associated with these effects are largely unknown. In this study, we characterized gene expression profiles in the prefrontal cortex, striatum, hypothalamus, amygdala and ventral tegmental area of the rat brain in response to subacute and chronic systemic nicotine administration using a pathway-focused microarray developed in this laboratory that contains 638 sequence-verified genes representing broad, yet targeted, biological functions. By comparing the regional effects of nicotine treatment on gene expression levels, we derived the expression profiles of targeted genes and gene families responding to the new environment created by nicotine throughout the complex connections of the CNS. While the expression of many genes was modulated by nicotine in several regions, only a few were co-modulated in multiple brain regions, suggesting region-specific transcriptional responses. Cluster analysis of significantly altered genes within each brain region over the course of nicotine treatment indicated the genes could be grouped into clusters. Subsequent ANOVA analysis demonstrated these clusters within each brain region to be significantly different at most time points. The clusters were comprised of broad functional groups, such as signaling, neurotransmission and protein modifications, demonstrating unique expression patterns within each region. Using a systematic approach to compare the different regional responses to nicotine administration will eventually provide a better understanding of how the different brain regions responding to this drug.
Brain Res Mol Brain Res 2004 Dec 20
PMID:Time-dependent changes in transcriptional profiles within five rat brain regions in response to nicotine treatment. 1558 56

Before the discovery of HFE, reports suggested that hemochromatosis patients with the ancestral haplotype (or some element thereof) have more severe iron overload than those without the haplotype. We performed univariate and multivariate analyses of the relationships of human leukocyte antigen (HLA)-A*03 and HLA haplotype A*03-B*07 to iron measures (serum iron concentration, transferrin saturation, and serum ferritin concentration at diagnosis and units of phlebotomy to achieve iron depletion) in hemochromatosis probands homozygous for HFE C282Y diagnosed in medical care. Iron overload was defined by demonstration of hepatic iron index of > or =1.9 or removal of > or =2.0 g Fe by therapeutic phlebotomy. We tabulated the phenotype frequencies of HLA-A*03 and the frequencies of common HLA haplotypes A*01-B*08, A*02-B*44, A*03-B*07, and A*03-B*14 in three groups of white adults: (1) 141 hemochromatosis probands with C282Y homozygosity; (2) 195 index cases with IgG subclass deficiency (IgGSD) or common variable immunodeficiency (CVID), disorders typically linked to Ch6p, and (3) 750 control subjects. Among probands, 86 men and 42 women had iron overload. Frequencies of HLA-A and -B alleles in probands did not depart significantly from Hardy-Weinberg equilibrium. The phenotype frequency of A*03 did not differ significantly between men and women in the each of the respective three groups. The frequency of haplotype A*03-B*07 was greater in men than women with hemochromatosis (0.3081 vs. 0.1455; P = 0.0019). The frequency of A*03-B*014 was significantly greater in women than men with hemochromatosis (0.1182 vs. 0.0407, respectively; P = 0.0134). Mean values of most iron measures were not affected by numbers of copies of A*03 or by presence of A*03-B*07 in either men or women in univariate analysis. ANOVA models of sex, age at diagnosis, and all HLA alleles and haplotypes in probands were used to determine effects of these variables on iron measures. ANOVA models revealed that (1) there were no significant predictors for serum iron concentration; (2) B*14 is associated with higher transferrin saturation in women and lower transferrin saturation in men; (3) A*01-B*08 is associated with a trend of higher serum ferritin levels; and (4) A*03-B*14 is associated with exaggeration of the age-associated upward trend in units of phlebotomy to achieve iron depletion. In hemochromatosis probands with HFE C282Y homozygosity, we conclude that (1) disparate frequencies of HLA haplotypes A*03-B*07 and A*03-B*14 occur in men and women and (2) HLA-A*03 and HLA-A*03-B*07 are not independent variables associated with iron overload severity.
Blood Cells Mol Dis
PMID:HLA haplotype A*03-B*07 in hemochromatosis probands with HFE C282Y homozygosity: frequency disparity in men and women and lack of association with severity of iron overload. 1560 98

BACKGROUND: A circadian rhythm of symptoms has been reported in allergic rhinitis and some studies have shown the dosing time of antihistamines to be of importance for optimizing symptom relief in this disease. The objective of this study was to examine the efficacy of morning vs. evening dosing of the antihistamine desloratadine at different time points during the day. METHODS: Patients >/= 18 years, with seasonal allergic rhinitis received desloratadine 5 mg orally once daily in the morning (AM-group) or evening (PM-group) for two weeks. Rhinorrhea, nasal congestion, sneezing and eye symptoms were scored morning and evening. Wilcoxon rank sum and 2-way ANOVA test were used. RESULTS: Six-hundred and sixty-three patients were randomized; 336 in the AM-group; 327 in the PM-group. No statistically significant differences were seen between the AM and PM group at any time points. In the sub-groups with higher morning or evening total symptom score no difference in treatment efficacy was seen whether the dose was taken 12 or 24 hours before the higher score time. There was a circadian variation in baseline total symptom score; highest during daytime and lowest at night. The circadian variation in symptoms was reduced during treatment. This reduction was highest for daytime symptoms. CONCLUSIONS: A circadian rhythm was seen for most symptoms being more pronounced during daytime. This was less apparent after treatment with desloratadine. No statistically significant difference in efficacy was seen whether desloratadine was given in the morning or in the evening. This gives the patients more flexibility in choosing dosing time.
Clin Mol Allergy 2005 Feb 02
PMID:Morning versus evening dosing of desloratadine in seasonal allergic rhinitis: a randomized controlled study [ISRCTN23032971]. 1568

Exposing day 5 bovine morulae to reactive oxygen species induces a delayed degeneration of some blastocysts on day 8 post-insemination (pi) but without affecting the blastocyst rates. The aim of this study was to characterize the resisting and the degenerating population of blastocysts. The kinetics of degeneration of the embryos exposed to the two pro-oxidant agents: 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH) and buthionine sulfoximine (BSO) was evaluated using time-lapse cinematography. With both agents the first signs of degeneration appeared at day 7.5 pi but the duration of the degeneration process was shorter in presence of AAPH than BSO (4.2 vs. 12.5 hr, ANOVA, P < 0.05). The resisting blastocysts derived from morulae with a larger diameter (mean diameter: 161 vs. 154 microm, ANOVA, P < 0.05) and showed an earlier cavitation (135 vs. 142 hpi, P < 0.05) than the degenerating ones. The profile of protein neosynthesis at day 7 was not affected by the treatment. The proportion of male embryos was more important in the resisting than in the degenerating population (70 vs. 55%, chi2, P < 0.05) especially when the stress was induced by AAPH. The quality of the resisting embryos, measured by the total cell number and the rate of apoptosis, did not seem to be affected when compared to control embryos. In conclusion, resistance to oxidative stress seems related to the kinetics of development and/or the sex of the embryos. Resisting embryos apparently display a quality similar to untreated embryos.
Mol Reprod Dev 2005 Jul
PMID:Impact of pro-oxidant agents on the morula-blastocyst transition in bovine embryos. 1580 60

Recently, a second gene that codes for the rate-limiting enzyme in serotonin synthesis was found in brain, named tryptophan hydroxylase-2 (TPH-2). We sequenced overlapping segments (251 and 510 bp) of 5' monkey TPH-2 and questioned whether TPH-2 is regulated by estrogen (E) and progesterone (P) in serotonin neurons of macaques. Monkey TPH-2 was 97% homologous to human TPH-2 and 65% homologous to monkey TPH-1 in the coding region. Spayed monkeys were administered placebo, E-only, P-only, or E + P for 1 month via Silastic implants (n = 4/treatment) and the midbrain was utilized for TPH-2 in situ hybridization (ISH). Additional monkeys (n = 3/treatment) were used to determine the relative abundance of TPH-2 mRNA with quantitative (q) RT-PCR. In the ISH assay, all of the hormone treatments caused a significant and similar increase in TPH-2 mRNA optical density (fourfold; P < 0.004) and positive pixel area (twofold; P < 0.002) over spayed controls. Treatment with E or E + P for 1 month increased the relative abundance of TPH-2 mRNA over spayed controls in the qRT-PCR assay (ANOVA P < 0.05 and P < 0.007, respectively). In conclusion, ovarian steroids stimulate TPH-2 mRNA expression, which could in turn cause an increase in serotonin synthesis. This would impact many of the neural functions that are governed by serotonin.
Brain Res Mol Brain Res 2005 Apr 27
PMID:A second tryptophan hydroxylase isoform, TPH-2 mRNA, is increased by ovarian steroids in the raphe region of macaques. 1585 82

7-Hydroxy-metabolites of dehydroepiandrosterone (DHEA) and 3beta,17beta-androstenediol (AD) possess immunomodulatory and neuroprotective properties; therefore, the measurement of these steroids in patients with autoimmune diseases or disturbances in the CNS may be of interest. A gas chromatography-mass spectrometry (GC-MS) method for the determination of 7-hydroxy-metabolites of pregnenolone, DHEA, AD, and testosterone including the parent steroids was applied to serum samples from 12 adult men (27-66 years), 13 male adolescents (13-20 years), 5 boys (6-10 years), 15 women in the follicular phase of the menstrual cycle (22-45 years), 17 women in the luteal phase (22-45 years), and 4 girls (6-10 years). The steroids were age and sex dependent, but independent of the menstrual cycle. The ratio of the 7alpha-hydroxy-metabolites to their parent steroids were age dependent, exhibiting an increasing trend (p < 0.0001, ANOVA) from pregnenolone (5%) to AD (20%). The ratio of 7beta- to 7alpha-metabolites ranged from 0.6 to 1. These results are consistent with models suggesting 7alpha-hydroxylation of the parent steroid, conversion to a 7-oxo-steroid and finally to the 7beta-hydroxylated-metabolite. Partial correlations suggested that 7-hydroxylation might reduce the concentration of circulating androgens. Despite the three times lower concentration of AD-metabolites, their antiglucocorticoid, immunomodulatory, and neuroprotective effects may be comparable to that of DHEA based on their reported greater biological activity.
J Steroid Biochem Mol Biol 2005 Jul
PMID:The identification and simultaneous quantification of 7-hydroxylated metabolites of pregnenolone, dehydroepiandrosterone, 3beta,17beta-androstenediol, and testosterone in human serum using gas chromatography-mass spectrometry. 1590 98

Three purposes are presented in this study: (1) to study the in vivo regional dependent intestinal absorption of a P-gp substrate with high solubility and high permeability, (2) to study the gene expression difference in the various regions of the intestine, and (3) to study the contributions of P-gp or any other transporters for the absorption of a P-gp substrate. The in vivo permeability of verapamil and propranolol were determined by single-pass in situ intestinal perfusion in rat. The gene expression profiles were measured using Affymetrix GeneChip. Correlation analysis between drug in vivo permeability and expression of 3500 genes was performed with nonparametric bootstrap and ANOVA analysis. The permeability of verapamil and propranolol did not demonstrate regional dependency even though significant differences in gene expression were observed in various regions of the intestine. Verapamil permeability significantly correlates with propranolol permeability in both jejunum and ileum, but did not correlate with the permeability of other hydrophilic compounds (valacyclovir, acyclovir, and phenylalanine). Four different regions (duodenum, jejunum, ileum, and colon) showed distinct gene expression patterns with more than 70-499 genes showing at least 5-fold expression differences. Interestingly, P-gp expression is gradually increased by 6-fold from the duodenum to colon. Despite the distinct gene expression patterns in the various regions of the intestine, verapamil permeability did not correlate with any gene expression from 3500 expressed genes in the intestine. A 2-6-fold P-gp expression difference did not seem to associate verapamil permeability in the various intestinal regions in vivo. These data suggest that P-gp plays a minimal role in the in vivo intestinal absorption process of verapamil with high water solubility and high membrane permeability. The intestinal absorption of verapamil in vivo is primarily dominated by its high permeability. However, it is important to note that the findings in this paper do not undermine the importance of P-gp in oral drug bioavailability, drug disposition from the liver, drug efflux from the blood-brain barrier, and drug-drug interaction.
Mol Pharm
PMID:Permeability dominates in vivo intestinal absorption of P-gp substrate with high solubility and high permeability. 1605 36

Neuroimaging and post-mortem studies indicate that chronic alcohol use induces global changes in brain morphology, such as cortical and subcortical atrophy. Recent studies have shown that frontal lobe structures are specifically susceptible to alcohol-related brain damage and shrinkage in this area is largely due to a loss of white matter. This may explain the high incidence of cognitive dysfunction observed in alcoholics. Using a proteomics-based approach, changes in protein expression in the dorsolateral prefrontal region (BA9) white matter were identified in human alcoholic brains. Protein extracts from the BA9 white matter of 25 human brains (10 controls; eight uncomplicated alcoholics; six alcoholics complicated with hepatic cirrhosis; one reformed alcoholic) were separated using two-dimensional gel electrophoresis. Overall, changes in the relative expression of 60 proteins were identified (P<0.05, ANOVA) in the alcoholic BA9 white matter. In total, 18 protein spots have been identified using MALDI-TOF; including hNP22, alpha-internexin, transketolase, creatine kinase chain B, ubiquitin carboxy-terminal hydrolase L1 and glyceraldehyde-3-phosphate dehydrogenase. Several of these proteins have been previously implicated in alcohol-related disorders and brain damage. By identifying changes in protein expression in this region from alcoholics, hypotheses may draw upon more mechanistic explanations as to how chronic ethanol consumption causes white matter damage.
Mol Psychiatry 2006 Jan
PMID:Differential protein expression in the prefrontal white matter of human alcoholics: a proteomics study. 1617 12

Although 17beta-estradiol (E2) administration following trauma-hemorrhage (T-H) improves cardiac function in male rodents, it is not known whether the salutary effects of E2 are mediated via estrogen receptor (ER)-alpha or ER-beta, and whether cardiac heat shock proteins (Hsp) are affected by E2 administration. Male Sprague-Dawley rats underwent T-H (mean BP 40 mmHg for 90 min, then resuscitation). ER-alpha agonist propyl pyrazole triol (PPT) (5 microg/kg), ER-beta agonist diarylpropiolnitrile (DPN) (5 microg/kg), or vehicle (10% DMSO) was injected subcutaneously during resuscitation. At 24 h after T-H or sham operation, cardiac output (CO), stroke volume (SV), mean blood pressure, and +/- dP/dt max were measured (n=6 rats per group). Cardiac Hsp32, 60, 70, and 90 mRNA/protein expressions and heat shock factor (HSF)-1 DNA binding activity were determined. One-way ANOVA and Tukey's test were used for statistical analysis. CO, SV and +/- dP/dt(max) decreased significantly after T-H, however, administration of ER-beta agonist DPN after T-H restored the above parameters. Moreover, DPN treatment prevented T-H-mediated decrease in Hsp60 mRNA/protein and Hsp90 protein expressions in the heart. Hsp32 and Hsp70 mRNA/protein expression and HSF-1 DNA binding activity in the hearts were increased even above the shams in DPN treated T-H rats. In contrast, no significant change in the above parameters was observed in T-H rats treated with ER-alpha agonist PPT. Thus, the salutary effects of E2 on cardiac function are mediated via ER-beta and ER-beta-induced up-regulation of Hsp likely plays a significant role in the E2-mediated cardioprotection after T-H.
J Mol Cell Cardiol 2006 Jan
PMID:Mechanism of cardioprotection following trauma-hemorrhagic shock by a selective estrogen receptor-beta agonist: up-regulation of cardiac heat shock factor-1 and heat shock proteins. 1628 80

Although 17beta-estradiol (E2) administration after trauma-hemorrhage attenuates lung injury in male rodents, it is not known whether the salutary effects are mediated via estrogen receptor (ER)-alpha or ER-beta. We hypothesized that the salutary effects of E2 lung are mediated via ER-beta. Male Sprague-Dawley rats underwent trauma-hemorrhage (mean blood pressure 40 mmHg for 90 min, then resuscitation). E2 (50 microg/kg), ER-alpha agonist propyl pyrazole triol (PPT; 5 microg/kg), ER-beta agonist diarylpropiolnitrile (DPN; 5 microg/kg), or vehicle (10% DMSO) was injected subcutaneously during resuscitation. At 24 h after trauma-hemorrhage or sham operation, bronchoalveolar fluid (BALF) was collected for protein concentration, LDH activity, and nitrate/nitrite and IL-6 levels. Moreover, lung tissue was used for inducible nitric oxide synthase (iNOS) mRNA/protein expression, nitrate/nitrite and IL-6 levels, and wet/dry weight ratio (n = 6 rats/group). One-way ANOVA and Tukey's test were used for statistical analysis. The results indicated that E2 downregulated lung iNOS expression after trauma-hemorrhage. Protein concentration, LDH activity, and nitrate/nitrite and IL-6 levels in BALF and nitrate/nitrite and IL-6 levels in the lung increased significantly after trauma-hemorrhage; however, administration of DPN but not PPT significantly improved all parameters. Moreover, DPN treatment attenuated trauma-hemorrhage-mediated increase in iNOS mRNA/protein expression in the lung. In contrast, no significant change in the above parameters was observed with PPT. Thus the salutary effects of E2 on attenuation of lung injury are mediated via ER-beta, and ER-beta-induced downregulation of iNOS likely plays a significant role in the DPN-mediated lung protection after trauma-hemorrhage.
Am J Physiol Lung Cell Mol Physiol 2006 May
PMID:Salutary effects of estrogen receptor-beta agonist on lung injury after trauma-hemorrhage. 1636 51


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