Inhibition of cholesterol synthesis by 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoAR) inhibitors has been associated with an increase in intestinal cholesterol absorption. This study examined how HMG-CoAR inhibition by atorvastatin modulates expression of key genes involved in intestinal cholesterol metabolism. A crossover study was conducted in which 22 hyperlipidemic men received atorvastatin, 40 mg/day, or placebo, each for 12 weeks. Gene expression was assessed by real-time PCR using duodenal biopsy samples obtained at the end of each phase of treatment. Treatment with atorvastatin was associated with a 76% reduction in lathosterol and significant increases in sitosterol (70%). Atorvastatin significantly increased intestinal mRNA levels of HMG-CoAR (59%), LDL receptor (LDLR) (52%), PCSK9 (187%), SREBP-2 (44%), and HNF-4α (13%). Furthermore, atorvastatin significantly increased intestinal mRNA levels of NPC1L1 by 19% and decreased mRNA levels of both ABCG5 and ABCG8 by 14%. Positive correlations were observed between changes in SREBP-2 and HNF-4α expression and concurrent changes in the intestinal mRNA levels of HMG-CoAR, LDLR, and NPC1L1. These results indicate that HMG-CoAR inhibition with atorvastatin stimulates the intestinal expression of NPC1L1, LDLR, and PCSK9; increases cholesterol absorption; and reduces expression of ABCG5/8; these effects are most likely mediated by upregulation of the transcription factors SREBP-2 and HNF-4α.

Galactose consumption as the only carbohydrate source results in little increase in plasma glucose and insulin concentrations when compared with fasting. Lower insulin might promote endogenous lipolysis during meal absorption, which may facilitate fat loss.

The main objective of this study was to examine if cobalt (Co) reduces Δ(9) -desaturase indices in milk and blood lipids in sows. The experimental design consisted of a repeated measurement consisting of a pre-treatment period of a minimum of 9 days, a treatment period of 5 days and a post-treatment period of 6 days. Experimental animals consisted of 10 lactating sows; five sows had an intramuscular injection of 59 mg Co diluted in 5 ml 0.9% saline solution twice a day, whereas the other five had an intramuscular injection of 5 ml 0.9% saline solution twice a day as a control. Milk Δ(9) -desaturase indices for cis-9 18:1, cis-9 16:1 and cis-9 14:1 were significantly reduced (p < 0.0001) as a result of the Co-treatment, contrasting with the plasma Δ(9) -desaturase indices, which were unaffected. Potential mechanisms explaining how Co might reduce milk Δ(9) -desaturase indices are discussed. Moreover, the toxicological level of Co and potential implications of using Co-ethylenediaminetetraacetic acid as a liquid marker in digestibility experiments are addressed.

Dietary (n-3) fatty acids from fish oil have been used to modulate immune function in many mammalian species. Together, dietary antioxidants and behavioral enrichment have been shown to enhance neutrophil phagocytosis in geriatric Beagle dogs. The purpose of this study was to further investigate the effects of vitamins E and C, in combination with dietary fish oil, on neutrophil mediated bacterial killing, and on transcript levels of selected neutrophil mRNA. Fifty adult Beagle dogs were randomized into five dietary treatment groups for 60 days. All foods were complete and balanced and met the nutrient profiles of AAFCO for adult dogs. For 60 days before study initiation, dogs consumed a pretrial food that contained 74 IU/kg vitamin E and 0 mg/kg vitamin C. The five experimental foods were confirmed by analytical methods to contain ≥640 IU/kg vitamin E and 130 mg/kg vitamin C (as fed). Experimental foods ranged from low levels of EPA and DHA (pretrial food and lowest experimental food had 0.01% EPA and no detectable DHA) to the highest experimental food with 0.25% EPA and 0.17% DHA. Ex vivo bactericidal activity of activated, peripheral-blood neutrophils against Lactococcus lactis was determined after 1 h incubation. Bactericidal activity was calculated as a percentage of control values (bacteria incubated in media without neutrophils). Transcript levels of genes involved in neutrophil-mediated immune functions were determined by real-time qPCR. Dogs in all treatment groups had increased serum vitamin E concentration (P<0.01). After consuming experimental food for 60 days, neutrophils from dogs in all 5 treatment groups also had increased bactericidal activity (P<0.01). Dietary fish oil however, had no effect on bactericidal activity. Stepwise multiple regression analysis demonstrated that the change in neutrophil mediated bacterial killing was significantly correlated to changes in gene expression of interleukin-8 receptor (IL-8R), interleukin converting enzyme (ICE), and myeloperoxidase (MPO; r(2)=0.33; P=0.003). When stepwise multiple regression analysis was performed considering each mRNA as a dependent variable and change in selected individual and summed fatty acid concentrations as independent variables, change in the ratio of saturated fatty acids (SFA) to polyunsaturated fatty acids (PUFA) was significant (P≤0.05) in the mRNA regression analyses for IL-8R, ICE, MPO, and cyclooxygenase-2. In summary, circulating neutrophils from dogs fed diets enriched in vitamins E and C had significantly increased bactericidal activity as well as altered gene expression. Change in SFA to PUFA ratio also altered neutrophil gene expression.

Atorvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the rate-limiting enzyme in cholesterol synthesis, lowers plasma cholesterol and triglyceride (TG) levels dose dependently. The aim of this study was to investigate the molecular mechanism(s) of this decrease in plasma TG levels in atorvastatin-treated subjects.

Aerobic training is related to an increase in blood oxidation markers. The purpose of the present study was to investigate the antioxidant capacity of Lippia citriodora extracts (PLX(®) ) on plasma and blood cell oxidative status of university students beginning a 21 days aerobic training routine (3 days/week). Using a double-blind design, 15 male athletes (21 ± 2.1 years) were assigned to a group consuming 1.8 g/day of the plant extract (PLX(®) -group) or a placebo (PLB-group). Two blood extractions were performed at day 0 and 21, from which lymphocytes, erythrocytes and plasma were isolated. Several circulating parameters, antioxidant enzyme activities and oxidative stress markers were measured. The PLX(®) -group displayed an increased HDL-cholesterol, a modest decrease in erythrocyte number and an increased circulating urea. Activation of glutathione (GSH)-reductase was observed in erythrocytes and lymphocytes of PLX(®) -group, accompanied by lower levels of oxidative stress markers, such as malondialdehyde and protein carbonyls in plasma. The antioxidant action exerted by PLX(®) on GSH-reductase seems to be post-translational and mainly due to verbascoside, a phenylpropanoid that represents 10% (w/w) of extract content. In conclusion, PLX(®) shows antioxidant properties that could play an important role in modulating GSH-reductase activity in lymphocytes and erythrocytes and protecting plasma from exercise oxidative damage.

The molecular regulation of the trypsin activity and the effects of corn gluten meal (CGM) on the trypsin activity and gene expression in Fugu obscurus were examined. The fish were fed with diets containing 0, 50, 100, 150, and 200 g kg⁻¹ CGM for 60 days. The trypsin activity and mRNA levels in the intestine, stomach, and hepatopancreas were measured before and after the experimental feeding. Enzyme activity was highest in the intestine, and mRNA expression was highest in the hepatopancreas prior to feeding the experimental diets. The effect of dietary CGM on the trypsin activity was dependent on the concentration. Enzyme activity was significantly lower in the hepatopancreas and stomach of the 200 g kg⁻¹ treatment group than in control group. In contrast, activity was enhanced in the stomach of the 100 g kg⁻¹ treatment group. Different amounts of CGM in the diets also resulted in significant changes in the trypsin mRNA levels in all three tissues. The trypsin mRNA expression in stomach, hepatopancreas, and intestine increased with increasing CGM from 0 to 10% and decreased with increasing CGM from 10 to 20%. The trypsin mRNA expression was highest in the 100 g kg⁻¹ treatment group, which was significantly higher than that of in the control. In addition, the changes in the trypsin mRNA expression levels were not reflected by changes in the trypsin activity. Our results suggest that the trypsin activity is regulated not only at the transcription level but also during translation and posttranslational modification.

NSAIDs are widely used in the treatment of inflammatory diseases as well as of tendon diseases associated with pain in sports and labor. However, the effect of NSAID intake, and thus blockade of PGE(2) production, on the tendon tissue adaptation is unknown. The purpose of the present study was to elucidate the possible effects of NSAID intake on healthy tendon collagen turnover in relation to a strenuous bout of endurance exercise. Fifteen healthy young men were randomly assigned into two experimental groups, with one group receiving indomethacin (oral 2 × 100 mg Confortid daily for 7 days; NSAID; n = 7) and a placebo group (n = 8). Both groups were exposed to a prolonged bout of running (36 km). The collagen synthesis NH₂-terminal propeptide of type I (PINP) and PGE₂ concentrations were measured before and 72 h following the run in the patella tendon by microdialysis. The peritendinous concentrations of PINP increased significantly in the placebo group as a result of the run, as shown previously. PGE₂ levels were significantly decreased 72 h after the run compared with basal levels in the subjects treated with NSAID and unchanged in the placebo group. The NSAID intake abolished the adaptive increase in collagen synthesis in the patella tendon found in the placebo group in response to the prolonged exercise (P < 0.05). The present study demonstrates that intake of NSAID decreased interstitial PGE₂ and abolished the exercise-induced adaptive increase in collagen synthesis in human tendons.

The question whether epidermal growth factor (EGF)-induced receptor endocytosis requires the prior autophosphorylation via the EGF receptor (EGFR) kinase domain has been a matter of long-standing debate. In the airway epithelial cell line NCI-H292, the EGFR kinase domain inhibitor BIBW 2948 BS was found to inhibit both autophosphorylation and subsequent internalization of the endogenous EGFR with similar IC₅₀ values. Applying an ex vivo EGFR internalization assay in a clinical study, the in vivo effect of inhalatively administered BIBW 2948 BS was determined directly at the targeted receptor in airway tissues from COPD patients. In these experiments, the in vivo inhibition of the EGFR kinase domain prevented the EGF-induced internalization of EGFR.

Lower respiratory tract infections due to respiratory syncytial virus (RSV) are associated with development of bronchiolitis obliterans syndrome in lung transplant (LTX) recipients. ALN-RSV01 is a small interfering RNA targeting RSV replication.

Prior research shows that menopause is associated with changes in cognition in some older women. However, how estrogen loss and subsequent estrogen treatment affects cognition and particularly the underlying brain processes responsible for any cognitive changes is less well understood. We examined the ability of estradiol to modulate the manipulation of information in working memory and related brain activation in postmenopausal women. Twenty healthy postmenopausal women (mean age (SD)=59.13 (5.5)) were randomly assigned to three months of 1mg oral 17-β estradiol or placebo. At baseline and three months later each woman completed a visual verbal N-back sequential letter test of working memory during functional magnetic resonance imaging (fMRI). The fMRI data showed that women who were treated with estradiol for three months had increased frontal activation during the more difficult working memory load conditions compared to women treated with placebo. Performance on the verbal working memory task showed no difference between estradiol and placebo treated subjects. These data are consistent with prior work showing increases in frontal activation on memory tasks after estrogen treatment. However, this is the first study to show that estrogen-induced increases in brain activity were tied to cognitive load during a verbal working memory task. These data suggest that estradiol treatment effects on cognition may be in part produced through modulation of frontal lobe functioning under difficult task conditions.

Increased levels of activated T cells are a hallmark of the chronic stage of human immunodeficiency virus (HIV) infection and are highly correlated with HIV disease progression. We evaluated chloroquine (CQ) as a potential therapy to reduce immune activation during HIV infection. We found that the frequency of CD38(+) HLA-DR(+) CD8 T cells, as well as Ki-67 expression in CD8 and CD4 T cells, was significantly reduced during CQ treatment. Our data indicate that treatment with CQ reduces systemic T-cell immune activation and, thus, that its use may be beneficial for certain groups of HIV-infected individuals.

We examined in a prospective, randomized, international clinical trial the performance of a previously defined 30-gene predictor (DLDA-30) of pathologic complete response (pCR) to preoperative weekly paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide (T/FAC) chemotherapy, and assessed if DLDA-30 also predicts increased sensitivity to FAC-only chemotherapy. We compared the pCR rates after T/FAC versus FACx6 preoperative chemotherapy. We also did an exploratory analysis to identify novel candidate genes that differentially predict response in the two treatment arms.

The aim of this study was to investigate the possible effect of somatostatin on the liver function of recipients undergoing living donor liver transplantation.

Valproic acid (VPA) has demonstrated potential as a therapeutic candidate for spinal muscular atrophy (SMA) in vitro and in vivo.

Arginine Vasopressin modulates complex social and sexual behavior by enhancing social recognition, pair bonding, and aggression in non-human mammals. The influence of Arginine Vasopressin in human social and sexual behavior is, however, yet to be fully understood. We evaluated whether Arginine Vasopressin nasal spray facilitated recognition of positive and negative social and sexual stimuli over non-social stimuli. We used a recognition task that has already been shown to be sensitive to the influence of Oxytocin nasal spray (Unkelbach et al., 2008). In a double-blind, randomized, placebo-controlled, between-subjects design, 41 healthy male volunteers were administered Arginine Vasopressin (20 IU) or a placebo nasal spray after a 45 min wait period and then completed the recognition task. Results showed that the participants administered Arginine Vasopressin nasal spray were faster to detect sexual words over other types of words. This effect appeared for both positively and negatively valenced words. Results demonstrate for the first time that Arginine Vasopressin selectively enhances human cognition for sexual stimuli, regardless of valence. They further extend animal and human genetic studies linking Arginine Vasopressin to sexual behavior in males. Findings suggest an important cognitive mechanism that could enhance sexual behaviors in humans.

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase activity and hence PG production. However, the ability of NSAIDs to ameliorate pain and tenderness does not prevent disease progression in rheumatoid arthritis, a disease whose pathogenesis is linked to the presence of proinflammatory cytokines, such as TNF-alpha. To understand this observation, we have examined the effect of NSAIDs on the production of clinically validated proinflammatory cytokines. We show that a variety of NSAIDs superinduce production of TNF from human peripheral blood monocytes and rheumatoid synovial membrane cultures. A randomized, double-blinded, crossover, placebo-controlled trial in healthy human volunteers also revealed that the NSAID drug celecoxib increased LPS-induced TNF production in whole blood. NSAID-mediated increases in TNF are reversed by either the addition of exogenous PGE(2) or by a PGE(2) EP2 receptor agonist, revealing that PGE(2) signaling via its EP2 receptor provides a valuable mechanism for controlling excess TNF production. Thus, by reducing the level of PGE(2), NSAIDs can increase TNF production and may exacerbate the proinflammatory environment both within the rheumatoid arthritis joint and the systemic environment.

beta-1,4-Mannobiose (MNB) supplementation has been shown to prevent Salmonella Enteritidis infection in broilers by improving Salmonella Enteritidis clearance and increasing IgA production. This study examined in detail the gut immunomodulatory activity of MNB using microarray and real-time quantitative PCR analysis. One-day-old chicks were orally administered 0.1% (wt/wt) MNB 3 times a week for 28 d. Control birds received vehicle alone. Body weights and fecal IgA levels were monitored weekly. On d 28, spleen and bursa of Fabricius were removed and weights were recorded; samples of ileum, jejunum, cecum, spleen, thymus, and bursa of Fabricius were collected for histological examination; and ileum samples were collected for RNA extraction. No significant difference in BW or organ weights was observed between MNB-treated and untreated control birds, and no histological abnormalities were observed in any of the tissues examined. The MNB-treated chickens had significantly higher levels of fecal IgA over all 4 wk when compared with control birds. Microarray and reverse transcription PCR analysis revealed the upregulation of several genes involved in immune responses, including those involved in antigen recognition, processing and presentation (MHC class I and II), interferon-related genes, and genes involved in host defense. These results provide insight into the mechanism of action of dietary MNB in the intestine and confirm that MNB acts as a potent immune-modulating agent, exerting combined effects on the intestinal immune system.

Because both micronutrients and antimicrobial peptides protect against diarrhea, we looked for an effect on intestinal antimicrobial peptide gene expression during a randomized controlled trial of multiple micronutrient (MM) supplementation.

The mechanisms by which testosterone increases hemoglobin and hematocrit are unknown.