Tocopherols have biphasic, proangiogenic and antiangiogenic therapeutic effects. The objective of this clinical trial was to clarify tocopherol's placental angiogenic potential in late pregnant ewes following oral supplementation.

Nonsense (premature stop codon) mutations in mRNA for the cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis (CF) in approximately 10% of patients. Ataluren (PTC124) is an oral drug that permits ribosomes to readthrough premature stop codons in mRNA to produce functional protein.

Pravastatin increases the plasma adiponectin level. We examined whether this is a statins' class effect or specific to pravastatin. Of 50 patients undergoing cardiac surgery for coronary artery disease (CAD, n = 36) and valvular heart disease (VHD, n = 14), 23 with CAD and serum LDL-cholesterol level >100 mg/dL were randomized to pravastatin at 10 mg/day (PRAVA, n = 12) or rosuvastatin at 2.5 mg/day (ROSUVA, n = 11) for 2 months, and the other 13 with CAD and LDL-cholesterol ≤100 mg/dL were not treated with statin (Non-statin, n = 13). Patients with VHD did not have CAD and were not treated with statin. Blood was sampled at baseline and surgery. Visceral (VIS) and subcutaneous (SC) adipose tissues were harvested during surgery. At baseline, the plasma adiponectin level was low in patients with CAD compared with that of patients with VHD. At surgery, adiponectin level in PRAVA was increased to the level in VHD, whereas those in ROSUVA and Non-statin were unchanged. VIS contents and gene expressions of adiponectin in PRAVA and VHD were similar to each other and were both higher than those in Non-statin and ROSUVA. SC content and gene expression of adiponectin were similar among 4 groups. Protein carbonyl (PC) level, an indicator of oxidative stress, in VIS was lower in PRAVA and VHD than in ROSUVA and Non-statin. There was a negative correlation between the plasma adiponectin and VIS PC levels (r = -0.41, P < 0.05). Thus, pravastatin increases adiponectin generation, whereas rosuvastatin does not.

Of 37 multiple sclerosis patients, 19 suboptimal responders were randomized to 375 (n=12) or 250µg (n=7) interferon (IFN)-β-1b. mRNA levels of 23 cytokines, chemokines, and chemokine receptors were quantified by TaqMan low-density array (TLDA) real-time polymerase chain reaction. Better treatment responses or increased IFN-β doses were associated with elevated IL-10 and TGF-β and decreased CXCL10, IL-18, IFN-γ, and TNF-α transcript levels. Adjusting for dose, poor treatment responses resulted in a 4-fold increase in CXCL10 and IFN-γ expression (Mantel-Haenszel RR=3.74, p<0.0001). CXCL10 and IFN-γ mRNA levels were reliable indicators of treatment response. TLDA can be used to tailor IFN-β-1b therapy.

To investigate the effect of mifepristone on gene expression of human chorionic villi in early pregnancy, nine women were recruited into a randomised controlled trial. All subjects were healthy women who had regular menstrual cycles and sought termination of pregnancy up to 40 days gestational age. In the test group, gestational sacs were taken by vacuum aspiration of the uterus 24 h after a single dose of 150 mg mifepristone was administered. Chorionic villi were collected and frozen in liquid nitrogen. The control samples were collected using the same method from the women without administration of mifepristone. The gene expressions of villus were monitored by human cDNA microarrays. It is found that the expressions of 262 transcripts were significantly altered in the test group. Gene ontology and pathways analyses were conducted to further analyse these genes. Many of these genes are known to play potentially an important role in the placentation and the molecular regulation of maternal-fetal interface. Therefore, it is suggested that the placental development and microenvironment of the maternal-fetal interface were interfered by administration of mifepristone. These data provide insight into the molecular mechanism about medical abortion induced by mifepristone.

Spinal cord stimulation (SCS) is a well-established treatment for neuropathic pain; nevertheless, 40% of patients fail to obtain satisfactory pain relief and in many patients, the effect tends to diminish with time. Based on animal experiments, intrathecal baclofen was previously introduced clinically to enhance suboptimal SCS effects. Later animal experiments demonstrated similar data for clonidine. The aim of this study was to elucidate whether intrathecal clonidine or baclofen enhances the effect of SCS in neuropathic pain patients in whom the pain relieving-effect of SCS is inadequate.

Resveratrol have been shown to exert an antiinflammatory and antiaging effects in vitro and in animal models.

The TLR4 (Toll-like receptor 4) signal plays an important role in immunity in CAD (coronary artery disease). miR-146a/b (where miR is microRNA) regulates the TLR4 downstream molecules IRAK1 (interleukin-1-receptor-associated kinase 1) and TRAF6 (tumour-necrosis-factor-receptor-associated factor 6). It has also been reported that statins and RAS (renin-angiotensin system) inhibition and have anti-atherosclerotic properties. In the present study, we have investigated whether miR-146a/b was expressed with the TLR4 signal in CAD patients, and whether combined treatment with a statin and RAS inhibition might affect these levels. A total of 66 patients with CAD and 33 subjects without CAD (non-CAD) were enrolled. Patients with CAD were randomized to 12 months of combined treatment with atorvastatin and telmisartan [an ARB (angiotensin II receptor blocker)] or atorvastatin and enalapril [an ACEI (angiotensin-converting enzyme inhibitor)]. PBMCs (peripheral blood mononuclear cells) were obtained from peripheral blood at baseline and after 12 months. Levels of miR-146a/b, IRAK1 mRNA, TRAF6 mRNA and TLR4 mRNA/TLR4 protein were significantly higher in the CAD group than in the non-CAD group (all P<0.01). Levels of miR-146a/b were positively correlated with IRAK1 mRNA and TRAF6 mRNA levels. After 12 months of treatment, these levels were markedly decreased in the ARB and ACEI groups, with the decrease in the ARB group being greater than that in the ACEI group (all P<0.05). In our 12-month follow-up study, high levels of miR-146a and TLR4 mRNA/TLR4 protein at baseline were independent predictors of cardiac events. The present study demonstrates that combined treatment with an ARB and a statin decreases miR-146a/b and the TLR4 signal in CAD patients, possibly contributing to the anti-atherogenic effects of ARBs and statins in this disorder.

The objective was to investigate if Banding or Burdizzo castration of bulls would alter the gene expression profile of a range of peripheral leukocyte inflammatory cytokines (IL-1, IL-6, IL-8, IL-10, interferon-γ and tumor necrosis factor-α) and to determine if the administration of carprofen (C) before castration would affect the expression of these genes. Thirty Holstein-Friesian bulls (5.5 months; Mean 191±(SEM) 3.7 kg) were blocked by weight and randomly assigned to one of five treatments: (1) untreated control (CON); (2) Banding castration at 0 min (BAND); (3) BAND following an i.v. injection of 1.4 mg/kg BW of carprofen (C) at -20 min (BAND+C); (4) Burdizzo castration at 0 min (BURD); or (5) BURD following 1.4 mg/kg BW of carprofen at -20 min (BURD+C). Blood samples were collected at 1 h before castration and 6, 24 and 48 h post-castration for routine hematology and quantitative real-time PCR analysis of cytokine gene expression analysis. Generally, there were no differences (P>0.05) among treatment groups in hematological variables following castration. Cortisol concentrations were unchanged throughout the experimental period in CON bulls. BURD animals had greater cortisol concentrations than BAND and CON animals at 6 h post treatment. Transitory effects were observed only in the expression of IL-6 and TNF-α. The relative expression of IL-6 was greater in the BURD than in the BAND treatment (P<0.05) at 24 h post-castration and was greater in the BURD+C group than in the BURD group (P<0.05) at 48 h. The relative expression of TNF-α was greater in BAND than in the BURD group (P<0.05) at 48 h. In conclusion, these findings indicate that Banding or Burdizzo castration did not have any major effect on peripheral leukocyte inflammatory cytokine gene expression; Banding castration caused a greater pro-inflammatory cytokine gene expression reaction than Burdizzo castration and carprofen administration can affect IL-6 gene expression levels in BURD castrated animals.

This study examined the effect of acetate on endothelial nitric oxide synthase (eNOS) in human umbilical vein endothelial cells (HUVECs) by immunoblotting assay and the ability of acetic acid to upregulate flow-mediated vasodilatation in humans. In HUVECs, acetate induced a biphasic increase in the phosphorylated form of eNOS. The amount of phosphorylated eNOS was significantly increased by exposure to 200 mumol/l acetate for 20 min (early phase) and for 4 h (late phase). The inhibitors of cAMP-dependent protein kinase (PKA) and AMP-activated protein kinase (AMPK) blocked acetate-induced eNOS phosphorylation in the early and the late phase respectively. Furthermore, in postmenopausal women, maximum forearm blood flow (FBF) in response to shear stress increased in the vinegar (acetic acid) administered group compared to the placebo group. These results suggest that acetic acid-induced eNOS phosphorylation contributes to upregulation of flow-mediated vasodilatation in humans.

Prospective studies indicate that tomato consumers are protected against prostate cancer. Lycopene has been hypothesized to be responsible for tomato health benefits.

Aromatase inhibitors (AI) have been established as a useful hormonal therapy in hormone receptor-expressing breast carcinoma. However, changes in tumor protein expression after exposure to AIs are not necessarily well understood. These changes may provide insight into how breast carcinomas respond or develop into a state of resistance towards AIs, and lead to the discovery of potential biomarkers to predict treatment responses.

In our research we focused our attention on the effect of the immune stress induced by bacterial endotoxin-lipopolysaccharide (LPS) on the hypothalamic-pituitary-gonadal axis (HPG) at the pituitary level. We examined the effect of intravenous (i.v.) LPS injection on luteinizing hormone (LH) and follicle-stimulating hormone (FSH) release from the anterior pituitary gland (AP) in anestrous ewes. The effect of endotoxin on prolactin and cortisol circulating levels was also determined. We also researched the effect of immune challenge on the previously mentioned pituitary hormones and their receptors genes expression in the AP. Our results demonstrate that i.v. LPS injection decreased the plasma concentration of LH (23%; p < 0.05) and stimulates cortisol (245%; p < 0.05) and prolactin (60%; p < 0.05) release but has no significant effect on the FSH release assayed during 6 h after LPS treatment in comparison with the control levels. The LPS administration affected the genes expression of gonadotropins' β-subunits, prolactin and their receptors in the AP. Endotoxin injection significantly decreased the LHβ and LH receptor (LHR) gene expression (60%, 64%; p < 0.01 respectively), increased the amount of mRNA encoding FSHβ, FSH receptor (FSHR) (124%, 0.05; 166%, p < 0.01; respectively), prolactin and prolactin receptor (PRLR) (50%, 47%, p < 0.01; respectively). The presented, results suggest that immune stress is a powerful modulator of the HPG axis at the pituitary level. The changes in LH secretion could be an effect of the processes occurring in the hypothalamus. However, the direct effect of immune mediators, prolactin, cortisol and other components of the hypothalamic pituitary-adrenal (HPA) axis on the activity of gonadotropes has to be considered as well. Those molecules could affect LH synthesis directly through a modulation at all stages of LHβ secretion as well as indirectly influencing the GnRHR expression and leading to reduced pituitary responsiveness to GnRH stimulation.

To evaluate the role of oxidative stress in prostate cancer risk, we analyzed serum levels of protein carbonyl groups in 1,808 prostate cancer cases and 1,805 controls, nested in the Prostate Cancer Prevention Trial, a randomized, placebo-controlled trial that found finasteride decreased prostate cancer risk. There were no significant differences in protein carbonyl levels in baseline samples between those later diagnosed with prostate cancer and those without at the end of study biopsy. Adjusted odds ratios and 95% confidence intervals (95% CI) for the 4th quartile of protein carbonyl level for the combined, placebo, and finasteride arms were 1.03 (95% CI, 0.85-1.24), 0.88 (95% CI, 0.69-1.12), and 1.27 (95% CI, 0.94-1.71), respectively. There were no significant associations between carbonyl level and risk when analyzing high-grade and low-grade disease separately, nor did finasteride affect protein oxidation levels. The results of this large nested case-control study do not support the hypothesis that oxidative stress, at least as measured by protein carbonyl level, plays a role in prostate cancer.

To study the effectiveness of clomiphene citrate (CC) in preventing a premature LH surge during controlled ovarian stimulation in women undergoing assisted reproduction.

To evaluate the impact of two different luteal phase support protocols on gene expression of extracellular matrix (ECM) proteins and adhesion molecules in the human endometrium.

The study was designed to test the hypothesis that granulosa cell (GC) gene expression response differs between recombinant FSH and human menopausal gonadotropin (hMG) stimulation regimens.

The aim of the study was to assess whether benefits associated with the traditional Mediterranean diet (TMD) and virgin olive oil (VOO) consumption could be mediated through changes in the expression of atherosclerosis-related genes. A randomized, parallel, controlled clinical trial in healthy volunteers (n=90) aged 20 to 50 yr was performed. Three-month intervention groups were as follows: 1) TMD with VOO (TMD+VOO), 2) TMD with washed virgin olive oil (TMD+WOO), and 3) control with participants' habitual diet. WOO was similar to VOO, but with a lower polyphenol content (55 vs. 328 mg/kg, respectively). TMD consumption decreased plasma oxidative and inflammatory status and the gene expression related with both inflammation [INF-gamma (INFgamma), Rho GTPase-activating protein15 (ARHGAP15), and interleukin-7 receptor (IL7R)] and oxidative stress [adrenergic beta(2)-receptor (ADRB2) and polymerase (DNA-directed) kappa (POLK)] in peripheral blood mononuclear cells. All effects, with the exception of the decrease in POLK expression, were particularly observed when VOO, rich in polyphenols, was present in the TMD dietary pattern. Our results indicate a significant role of olive oil polyphenols in the down-regulation of proatherogenic genes in the context of a TMD. In addition, the benefits associated with a TMD and olive oil polyphenol consumption on cardiovascular risk can be mediated through nutrigenomic effects.

The effects of tipranavir/ritonavir (TPV/r) on hepatic and intestinal P-glycoprotein (P-gp) and cytochrome P450 (CYP) enzyme activity were evaluated in 23 volunteers. The subjects received oral (p.o.) caffeine, warfarin + vitamin K, omeprazole, dextromethorphan, and midazolam and digoxin (p.o. and intravenous (i.v.)) at baseline, during the first three doses of TPV/r (500 mg/200 mg b.i.d.), and at steady state. Plasma area under the curve (AUC)(0-infinity) and urinary metabolite ratios were used for quantification of protein activities. A single dose of TPV/r had no effect on the activity of CYP1A2 and CYP2C9; it weakly inhibited CYP2C19 and P-gp; and it potently inhibited CYP2D6 and CYP3A. Multiple dosing produced weak induction of CYP1A2, moderate induction of CYP2C19, potent induction of intestinal P-gp, and potent inhibition of CYP2D6 and CYP3A, with no significant effects on CYP2C9 and hepatic P-gp. Several P450/transporter single-nucleotide polymorphisms correlated with the baseline phenotype but not with the extent of inhibition or induction. Although mixed induction and inhibition are present, this approach offers an understanding of drug interaction mechanisms and ultimately assists in optimizing the clinical use of TPV/r.

The possibility that maternal diets during gestation could affect growth and tissue development of offspring and program their later phenotype is an emerging challenge in pig production. The objective of the current study was to investigate the effects of contrasted protein levels in diets of pregnant sows on the proteomic features of subcutaneous adipose tissue (SCAT) of the offspring at birth and its possible persistence later in age. Sows were fed control (Con), low (LP), or high protein (HP) diets throughout gestation. A subset of piglets was killed at 1 d of age for SCAT sampling. The remaining piglets were cross-fostered to nonexperimental sows during lactation. They were fed standard diets during postweaning and fattening periods until 186 d of age. Modifications in SCAT protein abundance shortly after birth were investigated by 2-dimensional gel electrophoresis followed by mass spectrometry. A total of 65 spots were found differentially expressed (P <or= 0.10) in SCAT of 1-d-old experimental piglets vs. Con piglets. Proteins with a greater abundance in LP piglets compared with Con piglets were involved in pathways related to glucose and fatty acid metabolisms, lipid transport, and regulation of apoptosis. Upregulation of 5 proteins representative of these biological pathways in LP group vs. Con group were further validated (P < 0.05) by Western blot analyses. Furthermore, the specific activity of the key lipogenic enzyme fatty acid synthase was found greater (P = 0.06) in SCAT of 1-d-old LP piglets than in Con piglets. The main changes evidenced in SCAT of HP piglets compared with Con animals at 1 d of age rather concerned proteins putatively involved in AA metabolism or in protein turnover. Adipose tissue contents in some proteins that had displayed a greater (P <or= 0.10) abundance in experimental pigs compared with Con at d 1 (e.g., transaldolase, annexin II, and apolipoprotein A4) were, however, similar (P > 0.10) in the 3 groups at d 186 of age. Enolase 1 has less abundance (P < 0.05) in LP pigs compared with Con pigs at this stage. In conclusion, the proteomics tool has allowed the identification of early changes in various molecular pathways of SCAT in response to the levels of maternal protein supply during gestation.