Association of Proton Pump Inhibitor Use With Serum Biomarkers of Inflammation, Insulin Resistance, Cardiovascular Risk, and Renal Function.

BACKGROUND AND GOALS: Proton pump inhibitor (PPI) use has been associated with cardiovascular disease, chronic kidney disease, and dementia. Prior studies did not account for key confounders and little is known about the association of PPIs with serum biomarkers of inflammation, insulin resistance, cardiovascular risk, and renal function. Our aims were to investigate differences in these biomarkers between PPI users and nonusers. METHODS: Our data are from the National Health and Nutrition Examination Survey (NHANES), a complex cross-sectional multistage probability sample of the US civilian population. We used data on 5189 eligible adults aged 18 to 85 years. Appropriate survey commands were used and potential confounding variables (including BMI, duration of PPI use, use of other non-PPI medications, and health behaviors) were included in multivariable regression models assessing biomarker outcomes. RESULTS: PPI use was associated with differences in mean (±SE) fasting low-density lipoprotein (LDL) (by 11.7±3.7 mg/dL; P=0.006), and apolipoprotein B (by 7.6±2.6 mg/dL; P=0.01). PPI use was not associated with significant differences in total cholesterol (P=0.13), high-density lipoprotein (P=0.27), triglycerides (P=0.70), c-reactive protein (P=0.52), the homeostatic model assessment-insulin resistance (P=0.48), hemoglobin A1c (P=0.39), or homocysteine (P=0.87). PPI use was associated with a decrease in blood urea nitrogen (by 1.0±0.3 mg/dL; P=0.008) but not creatinine (P=0.38) or uric acid (P=0.34). CONCLUSION: PPI was not associated with clinically significant differences in serum biomarkers of inflammation, insulin resistance, cardiovascular risk, and renal function. Rather, increasing BMI was strongly associated with PPI use and clinically significant differences in these biomarkers.

Body mass index, age, and gender affect prep quality, sedation use, and procedure time during screening colonoscopy.

BACKGROUND: Body mass index (BMI), age, and gender influence colorectal cancer (CRC) and adenoma risk. Their effects on colonoscopy characteristics are unclear, but might inform the screening approach in patient subgroups. AIMS: The aims of this study were to assess the effect of BMI, age, and gender on prep quality, amount of sedation, procedure time, and adenoma prevalence for screening colonoscopy. METHODS: We conducted a review of 773 eligible colonoscopies performed for average-risk CRC screening. We performed multivariable regression analyses to assess the outcomes of prep quality, amount of fentanyl and midazolam used, procedure time, and the adenoma prevalence rate (APR). RESULTS: Obese patients were less likely (p = 0.01) to have a good or excellent prep, had similar procedure times, and received similar amounts of fentanyl and midazolam. Increasing age had no effect on prep quality or procedure time, but was associated with decreased fentanyl and midazolam (both p ≤ 0.001). Women had similar prep quality, longer procedure times (increased by 2.8 ± 0.7 min, p < 0.001) for colonoscopies in which no polyps were detected, and received more fentanyl and midazolam (both p = 0.01). Increasing BMI, increasing age, and male gender were associated with an increased APR. The APR for women aged 50-59 with a normal BMI was 17.9 %. CONCLUSIONS: Normal-weight females, particularly those under age 60, have the lowest APR but have longer procedure times and require higher amounts of sedation. Screening options other than colonoscopy might be well-suited to this population.

Association of Proton Pump Inhibitor (PPI) Use with Energy Intake, Physical Activity, and Weight Gain.

Studies suggest proton pump inhibitor (PPI) use impacts body weight regulation, though the effect of PPIs on energy intake, energy extraction, and energy expenditure is unknown. We used data on 3073 eligible adults from the National Health and Nutrition Examination Survey (NHANES). Medication use, energy intake, diet composition, and physical activity were extracted from NHANES. Multivariate regression models included confounding variables. Daily energy intake was similar between PPI users and non-users (p = 0.41). Diet composition was similar between the two groups, except that PPI users consumed a slightly greater proportion of calories from fat (34.5% vs. 33.2%; p = 0.02). PPI users rated themselves as being as physically active as their age/gender-matched peers and reported similar frequencies of walking or biking. However, PPI users were less likely to have participated in muscle-strengthening activities (OR: 0.53; 95% CI: 0.30-0.95). PPI users reported similar sedentary behaviors to non-users. Male PPI users had an increase in weight (of 1.52 ± 0.59 kg; p = 0.021) over the previous year compared to non-users, while female PPI users had a non-significant increase in weight. The potential mechanisms for PPI-associated weight gain are unclear as we did not find evidence for significant differences in energy intake or markers of energy expenditure.

Novel steroid receptor phyto-modulator compound a inhibits growth and survival of prostate cancer cells.

Androgen receptor (AR)- and glucocorticoid receptor (GR)- mediated signaling play opposite roles in prostate tumorigenesis: AR promotes prostate carcinoma (PC) development, whereas GR acts as a tumor suppressor. Compound A (CpdA) is a stable analogue of an aziridine precursor from the African shrub Salsola tuberculatiformis Botschantzev. It was shown recently that, in model cells, CpdA inhibits AR function and strongly enhances anti-inflammatory function of GR. We determined the effects of CpdA in prostate cells with different AR/GR status: (a) RWPE-1 cells (AR(low)/GR(low)), (b) PC3 and DU145 cells (GR(+)/AR(-)), (c) LNCaP cells (GR(-)/AR(+)), and (d) LNCaP-GR cells expressing both receptors. Similar to steroid hormones, CpdA induces nuclear translocation of both receptors in prostate cells. Despite this, CpdA inhibits DNA-binding and transactivation potential of AR. In addition, CpdA inhibits GR-mediated transactivation but induces GR transrepression via inhibition of several transcription factors, including nuclear factor-kappaB, AP-1, Ets-1, Elk-1, SRF, CRE/ATF, and NFATc. CpdA strongly decreases growth and induces caspase-dependent apoptosis in highly malignant PC3 and DU145 cells and in other AR/GR-expressing PC cells. The cytostatic effect of CpdA is receptor dependent: down-regulation of GR or AR expression drastically attenuates CpdA-induced PC cell growth inhibition. Finally, virtual docking analysis indicates that CpdA shares binding cavities in AR and GR ligand-binding domains with corresponding hormones and forms hydrogen bonds (H-bond) with the same amino acids that are involved in H-bond formation during steroid binding. Overall, our data suggest that CpdA is a unique dual-target steroid receptor modulator that has a high potential for PC therapy.

Proteomics as a tool for discovery: proteins implicated in Alzheimer's disease are highly expressed in normal pancreatic islets.

A proteomic analysis of islets was undertaken to determine the protein constituents of normal adult mouse islets. Unexpectedly, we identified several islet proteins that are associated with the pathogenesis of Alzheimer's disease. Some of these proteins had chaperone activity that is integral to proper protein folding. This group includes GRP78, valosin-containing protein, calreticulin, protein disulfide isomerase, DnaK, HSP70, HSP60, and TCP-1. Additionally, neuronal proteins key to coordinated neuronal guidance and survival were also identified in islets. This group includes proprotein convertase subtilisin, collapsin response mediator protein 2, ubiquinol-cytochrome c reductase core protein, L-3-hydroxyacyl-Coenzyme A dehydrogenase, glutamine synthetase, peroxiredoxin, and secretogogin. An important subset of the proteins identified here has not been reported previously in pancreatic islets. Abnormal activity of these proteins in brain may contribute to the pathogenesis of Alzheimer's disease, a neurodegenerative condition characterized by focal amyloid deposits with neurofibrillary tangles. The putative role of these proteins in Alzheimer's pathogenesis is intriguing given the possible clinical relationship and pathological similarity of Alzheimer's disease to type 2 diabetes. These findings have therefore led to the hypothesis that these proteins may also play a role in type 2 diabetes.