PrP C as a Transducer of Physiological and Pathological Signals.

After the discovery of prion phenomenon, the physiological role of the cellular prion protein (PrP C ) remained elusive. In the past decades, molecular and cellular analysis has shed some light regarding interactions and functions of PrP C in health and disease. PrP C , which is located mainly at the plasma membrane of neuronal cells attached by a glycosylphosphatidylinositol (GPI) anchor, can act as a receptor or transducer from external signaling. Although the precise role of PrP C remains elusive, a variety of functions have been proposed for this protein, namely, neuronal excitability and viability. Although many issues must be solved to clearly define the role of PrP C , its connection to the central nervous system (CNS) and to several misfolding-associated diseases makes PrP C an interesting pharmacological target. In a physiological context, several reports have proposed that PrP C modulates synaptic transmission, interacting with various proteins, namely, ion pumps, channels, and metabotropic receptors. PrP C has also been implicated in the pathophysiological cell signaling induced by ß-amyloid peptide that leads to synaptic dysfunction in the context of Alzheimer's disease (AD), as a mediator of Aß-induced cell toxicity. Additionally, it has been implicated in other proteinopathies as well. In this review, we aimed to analyze the role of PrP C as a transducer of physiological and pathological signaling.

Therapeutic Use of Vitamin C in Cancer: Physiological Considerations.

Since the early studies of William J. McCormick in the 1950s, vitamin C has been proposed as a candidate for the treatment of cancer. A number of reports have shown that pharmacological concentrations of vitamin C selectively kill cancer cells in vitro and decrease the growth rates of a number of human tumor xenografts in immunodeficient mice. However, up to the date there is still doubt regarding this possible therapeutic role of vitamin C in cancer, mainly because high dose administration in cancer patients has not showed a clear antitumor activity. These apparent controversial findings highlight the fact that we lack information on the interactions that occurs between cancer cells and vitamin C, and if these transformed cells can uptake, metabolize and compartmentalize vitamin C like normal human cells do. The role of SVCTs and GLUTs transporters, which uptake the reduced form and the oxidized form of vitamin C, respectively, has been recently highlighted in the context of cancer showing that the relationship between vitamin C and cancer might be more complex than previously thought. In this review, we analyze the state of art of the effect of vitamin C on cancer cells in vitro and in vivo, and relate it to the capacity of cancer cells in acquiring, metabolize and compartmentalize this nutrient, with its implications on the potential therapeutic role of vitamin C in cancer.

Antioxidant Effect of a Polyphenol-Rich Murtilla (Ugni molinae Turcz.) Extract and Its Effect on the Regulation of Metabolism in Refrigerated Boar Sperm.

The production of reactive oxygen species (ROS) in boar spermatozoa increases in refrigeration; this can have an impact on sperm quality and fertilization capacity. We evaluated the effect of polyphenol-rich aqueous extract of murtilla (Ugni molinae Turcz) on boar sperm stored at 17°C in order to reduce oxidative stress and improve sperm quality in the long term. Five experiments were performed: first, characterization of the polyphenol content from five genotypes of murtilla; second, determination of the genotype with the best antioxidant effect (MT-Ex); third, the antioxidant capacity on O2 - and lipid peroxidation; fourth, the influence of MT-Ex on motility, calcium movement, cAMP, and metabolic parameters; and fifth, analysis of long-term refrigeration. The average phenolic content was 344 ppm; gallic acid, catechin, quercetin, myricetin, and kaempferol were detected. All extracts evaluated presented a concentration-dependent antioxidant effect. MT-Ex reduces intracellular O2 -/peroxides but low lipid peroxidation. MT-Ex in nonstimulated ROS conditions reduces sperm motility, mitochondrial membrane potential, cAMP, and ATP, but the succinate dehydrogenase activity remained normal; also, we observed a reduction in calcium movement in in vitro sperm capacitation. The long-term analyses showed that MT-Ex improved sperm motility decay and reduced membrane damage and ROS at 168 h. Based on this study, we propose MT-Ex as a supplement in semen extenders.

Antioxidant and Vasodilator Activity of Ugni molinae Turcz. (Murtilla) and Its Modulatory Mechanism in Hypotensive Response.

Hypertension is a systemic condition with high morbidity and mortality rates worldwide, which poses an increased risk for cardiovascular diseases. In this study, we demonstrated the antioxidant and vasodilator activity of Ugni molinae Turcz. (Murtilla) fruit, a berry native to Chile and proposed models to explain its modulatory mechanism in hypotensive response. Murtilla fruits were cultivated in a germplasm bank and submitted to chemical and biological analyses. The phenolic compounds gallic acid, Catechin, Quercetin-3-ß-D-glucoside, Myricetin, Quercetin, and Kaempferol were identified. Murtilla extract did not generate toxic effects on human endothelial cells and had significant antioxidant activity against ROS production, lipid peroxidation, and superoxide anion production. Furthermore, it showed dose-dependent vasodilator activity in aortic rings in the presence of endothelium, whose hypotensive mechanism is partially mediated by nitric oxide synthase/guanylate cyclase and large-conductance calcium-dependent potassium channels. Murtilla fruits might potentially have beneficial effects on the management of cardiovascular diseases.

CKD Progression and Mortality among Hispanics and Non-Hispanics.

Although recommended approaches to CKD management are achieved less often in Hispanics than in non-Hispanics, whether long-term outcomes differ between these groups is unclear. In a prospective longitudinal analysis of participants enrolled into the Chronic Renal Insufficiency Cohort (CRIC) and Hispanic-CRIC Studies, we used Cox proportional hazards models to determine the association between race/ethnicity, CKD progression (50% eGFR loss or incident ESRD), incident ESRD, and all-cause mortality, and linear mixed-effects models to assess differences in eGFR slope. Among 3785 participants, 13% were Hispanic, 43% were non-Hispanic white (NHW), and 44% were non-Hispanic black (NHB). Over a median follow-up of 5.1 years for Hispanics and 6.8 years for non-Hispanics, 27.6% of all participants had CKD progression, 21.3% reached incident ESRD, and 18.3% died. Hispanics had significantly higher rates of CKD progression, incident ESRD, and mean annual decline in eGFR than did NHW (P<0.05) but not NHB. Hispanics had a mortality rate similar to that of NHW but lower than that of NHB (P<0.05). In adjusted analyses, the risk of CKD progression did not differ between Hispanics and NHW or NHB. However, among nondiabetic participants, compared with NHB, Hispanics had a lower risk of CKD progression (hazard ratio, 0.61; 95% confidence interval, 0.39 to 0.95) and incident ESRD (hazard ratio, 0.50; 95% confidence interval, 0.30 to 0.84). At higher levels of urine protein, Hispanics had a significantly lower risk of mortality than did non-Hispanics (P<0.05). Thus, important differences in CKD progression and mortality exist between Hispanics and non-Hispanics and may be affected by proteinuria and diabetes.

Association of N-terminal pro-B-type natriuretic peptide with left ventricular structure and function in chronic kidney disease (from the Chronic Renal Insufficiency Cohort [CRIC]).

We evaluated the cross-sectional associations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) with cardiac structural and functional abnormalities in a cohort of patients with chronic kidney disease without clinical heart failure, the Chronic Renal Insufficiency Cohort (n = 3,232). The associations of NT-proBNP with echocardiographically determined left ventricular (LV) mass and LV systolic and diastolic function were evaluated using multivariate logistic and linear regression models. Reclassification of participants' predicted risk of LV hypertrophy (LVH), systolic and diastolic dysfunction was performed using a category-free net reclassification improvement index that compared a clinical model with and without NT-proBNP. The median NT-proBNP was 126.6 pg/ml (interquartile range 55.5 to 303.7). The greatest quartile of NT-proBNP was associated with a nearly threefold odds of LVH (odds ratio 2.7, 95% confidence interval [CI] 1.8 to 4.0) and LV systolic dysfunction (odds ratio 2.7, 95% CI 1.7 to 4.5) and a twofold odds of diastolic dysfunction (odds ratio 2.0, 95% CI 1.3 to 2.9) in the fully adjusted models. When evaluated alone as a screening test, NT-proBNP functioned modestly for the detection of LVH (area under the curve 0.66) and LV systolic dysfunction (area under the curve 0.62) and poorly for the detection of diastolic dysfunction (area under the curve 0.51). However, when added to the clinical model, NT-proBNP significantly reclassified participants' likelihood of having LVH (net reclassification improvement 0.14, 95% CI 0.13-0.15; p <0.001) and LV systolic dysfunction (net reclassification improvement 0.28, 95% CI 0.27 to 0.30; p <0.001) but not diastolic dysfunction (net reclassification improvement 0.10, 95% CI 0.10 to 0.11; p = 0.07). In conclusion, in this large chronic kidney disease cohort without heart failure, NT-proBNP had strong associations with prevalent LVH and LV systolic dysfunction.

Plant protein intake is associated with fibroblast growth factor 23 and serum bicarbonate levels in patients with chronic kidney disease: the Chronic Renal Insufficiency Cohort study.

BACKGROUND: Protein from plant, as opposed to animal, sources may be preferred in chronic kidney disease (CKD) because of the lower bioavailability of phosphate and lower nonvolatile acid load. STUDY DESIGN: Observational cross-sectional study. SETTING AND PARTICIPANTS: A total of 2,938 participants with CKD and information on their dietary intake at the baseline visit in the Chronic Renal Insufficiency Cohort Study. PREDICTORS: Percentage of total protein intake from plant sources (percent plant protein) was determined by scoring individual food items using the National Cancer Institute Diet History Questionnaire (DHQ). OUTCOMES: Metabolic parameters, including serum phosphate, bicarbonate (HCO3), potassium, and albumin, plasma fibroblast growth factor 23 (FGF-23), and parathyroid hormone (PTH), and hemoglobin levels. MEASUREMENTS: We modeled the association between percent plant protein and metabolic parameters using linear regression. Models were adjusted for age, sex, race, diabetes status, body mass index, estimated glomerular filtration rate, income, smoking status, total energy intake, total protein intake, 24-hour urinary sodium concentration, use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and use of diuretics. RESULTS: Higher percent plant protein was associated with lower FGF-23 (P = .05) and higher HCO3 (P = .01) levels, but not with serum phosphate or parathyroid hormone concentrations (P = .9 and P = .5, respectively). Higher percent plant protein was not associated with higher serum potassium (P = .2), lower serum albumin (P = .2), or lower hemoglobin (P = .3) levels. The associations of percent plant protein with FGF-23 and HCO3 levels did not differ by diabetes status, sex, race, CKD stage (2/3 vs. 4/5), or total protein intake (≤0.8 g/kg/day vs. >0.8 g/kg/day; P-interaction >.10 for each). LIMITATIONS: This is a cross-sectional study; determination of percent plant protein using the Diet History Questionnaire has not been validated. CONCLUSIONS: Consumption of a higher percentage of protein from plant sources may lower FGF-23 and raise HCO3 levels in patients with CKD.

Soluble Aß(1-40) peptide increases excitatory neurotransmission and induces epileptiform activity in hippocampal neurons.

It is believed that amyloid-ß peptide (Aß), in its aggregated-oligomeric state, constitutes one of the neurotoxic factors involved in the pathogenesis of Alzheimer's disease. With the objective of studying a potential role of the peptide on synaptic transmission, we studied the effect of soluble Aß(1-40) on synaptic transmission in rat hippocampal neurons. Neurons incubated with 500 nM of Aß(1-40) peptide for 3 days presented higher levels of intracellular calcium transients, as evaluated by fluorimetric techniques. These effects of Aß were time and concentration dependent and were accompanied by increases in glutamatergic (0.8±0.2 Hz to 2.9±0.6 Hz), but not GABAergic, transmission. The analysis of pharmacologically isolated currents in treated neurons showed increases in both AMPA- and NMDA-mediated currents as compared to control. The effects of the peptide on the frequency of synaptic currents correlated well with increases in the number of SV2 puncta and of FM1-43 destaining, suggesting a presynaptic locus for the peptide. The data also shows that application of either Aß or bicuculline alone for 24 h was without effects on neurotransmission. However, their co-application induced an increase in synaptic transmission which was accompanied by synchronous discharges reminiscent to those produced by pro-convulsive drugs, such as bicuculline. In conclusion, these results suggest that the soluble form of Aß(1-40) participates in the regulation of synaptic transmission increasing excitability and producing a pre-epileptogenic state in hippocampal neurons.

The presence of glia stimulates the appearance of glycinergic synaptic transmission in spinal cord neurons.

Previous studies, using electrophysiological and fluorimetric analysis with a calcium sensitive dye, have shown that 5-7 DIV developing spinal cord neurons displayed high levels of glycinergic transmission. GABAergic and AMPAergic neurotransmission contributed much less to the overall transmission. Here, we show that culturing neurons in absence of a glia cell monolayer reduced the frequency of glycinergic spontaneous IPSCs (0.1 +/- 0.01 Hz), without altering the level of overall transmission (3 +/- 1.1 Hz). The predominant transmission was mediated by GABA(A) receptors (72% of total synaptic events). In addition, combination of bicuculline and CNQX blocked synaptically mediated calcium transients recorded with fluo-3. Furthermore, application of glycine revealed the presence of extrasynaptic receptors in these neurons (25 +/- 6 pA/pF). Culturing neurons on a glial cell monolayer increased the frequency of glycinergic currents (0.4 +/- 0.02 Hz), without changing the amplitude of the current (20 +/- 4 pA). The use of a glia-conditioned media reversed the effect of growing the neurons in a glia-deprived condition. These results indicate that the establishment of glycinergic transmission is dependent on the presence of a glia derived soluble factor. However, functional GlyRs were still able to insert in the neuronal membrane in a glia-independent manner.