Polyphenols and Their Impact on the Prevention of Neurodegenerative Diseases and Development.

It is well known that neurodegenerative diseases' development and progression are accelerated due to oxidative stress and inflammation, which result in impairment of mitochondrial function, cellular damage, and dysfunction of DNA repair systems. The increased consumption of antioxidants can postpone the development of these disorders and improve the quality of patients' lives who have already been diagnosed with neurodegenerative diseases. Prolonging life span in developed countries contributes to an increase in the incidence ratio of chronic age-related neurodegenerative disorders, such as PD (Parkinson's disease), AD (Alzheimer's disease), or numerous forms of age-related dementias. Dietary supplementation with neuroprotective plant-derived polyphenols might be considered an important element of healthy aging. Some polyphenols improve cognition, mood, visual functions, language, and verbal memory functions. Polyphenols bioavailability differs greatly from one compound to another and is determined by solubility, degree of polymerization, conjugation, or glycosylation resulting from chemical structure. It is still unclear which polyphenols are beneficial because their potential depends on efficient transport across the BBB (blood-brain barrier), bioavailability, and stability in the CNS (central nervous system). Polyphenols improve brain functions by having a direct impact on cells and processes in the CNS. For a direct effect, polyphenolic compounds must be able to overcome the BBB and accumulate in brain tissue. In this review, the latest achievements in studies (animal models and clinical trials) on the effect of polyphenols on brain activity and function are described. The beneficial impact of plant polyphenols on the brain may be summarized by their role in increasing brain plasticity and related cognition improvement. As reversible MAO (monoamine oxidase) inhibitors, polyphenols are mood modulators and improve neuronal self-being through an increase in dopamine, serotonin, and noradrenaline amounts in the brain tissue. After analyzing the prohealth effects of various eating patterns, it was postulated that their beneficial effects result from synergistic interactions between individual dietary components. Polyphenols act on the brain endothelial cells and improve the BBB's integrity and reduce inflammation, thus protecting the brain from additional injury during stroke or autoimmune diseases. Polyphenolic compounds are capable of lowering blood pressure and improving cerebral blood flow. Many studies have revealed that a nutritional model based on increased consumption of antioxidants has the potential to ameliorate the cognitive impairment associated with neurodegenerative disorders. Randomized clinical trials have also shown that the improvement of cognitive functions resulting from the consumption of foods rich in flavonoids is independent of age and health conditions. For therapeutic use, sufficient quantities of polyphenols must cross the BBB and reach the brain tissue in active form. An important issue in the direct action of polyphenols on the CNS is not only their penetration through the BBB, but also their brain metabolism and localization. The bioavailability of polyphenols is low. The most usual oral administration also conflicts with bioavailability. The main factors that limit this process and have an effect on therapeutic efficacy are: selective permeability across BBB, gastrointestinal transformations, poor absorption, rapid hepatic and colonic metabolism, and systemic elimination. Thus, phenolic compounds have inadequate bioavailability for human applications to have any beneficial effects. In recent years, new strategies have been attempted in order to exert cognitive benefits and neuroprotective effects. Converting polyphenols into nanostructures is one of the theories proposed to enhance their bioavailability. The following nanoscale delivery systems can be used to encapsulate polyphenols: nanocapsules, nanospheres, micelles, cyclodextrins, solid lipid nanoparticles, and liposomes. It results in great expectations for the wide-scale and effective use of polyphenols in the prevention of neurodegenerative diseases. Thus far, only natural polyphenols have been studied as neuroprotectors. Perhaps some modification of the chemical structure of a given polyphenol may increase its neuroprotective activity and transportation through the BBB. However, numerous questions should be answered before developing neuroprotective medications based on plant polyphenols.

The Presence of Caffeic Acid in Cerebrospinal Fluid: Evidence That Dietary Polyphenols Can Cross the Blood-Brain Barrier in Humans.

Epidemiological data indicate that a diet rich in plant polyphenols has a positive effect on brain functions, improving memory and cognition in humans. Direct activity of ingested phenolics on brain neurons may be one of plausible mechanisms explaining these data. This also suggests that some phenolics can cross the blood-brain barrier and be present in the brain or cerebrospinal fluid. We measured 12 phenolics (a combination of the solid-phase extraction technique with high-performance liquid chromatography) in cerebrospinal fluid and matched plasma samples from 28 patients undergoing diagnostic lumbar puncture due to neurological disorders. Homovanillic acid, 3-hydroxyphenyl acetic acid and caffeic acid were detectable in cerebrospinal fluid reaching concentrations (median; interquartile range) 0.18; 0.14 µmol/L, 4.35; 7.36 µmol/L and 0.02; 0.01 µmol/L, respectively. Plasma concentrations of caffeic acid (0.03; 0.01 µmol/L) did not correlate with those in cerebrospinal fluid (ρ = -0.109, p = 0.58). Because food (fruits and vegetables) is the only source of caffeic acid in human body fluids, our results indicate that the same dietary phenolics can cross blood-brain barrier in humans, and that transportation of caffeic acid through this barrier is not the result of simple or facilitated diffusion.

Intratumor heterogeneity and tissue distribution of KRAS mutation in non-small cell lung cancer: implications for detection of mutated KRAS oncogene in exhaled breath condensate.

PURPOSE: Mutated KRAS oncogene in exhaled breath condensate (EBC) can be a genetic marker of non-small cell lung cancer (NSCLC). However, a possibility of inhomogeneous distribution in cancer tissue and intratumor heterogeneity of KRAS mutation may decrease its significance. We investigated a status of KRAS point mutation and its sequence at codon 12 in 51 NSCLC patients after tumor resection. The comparison of KRAS mutation status between EBC-DNA and cancer tissue was performed in 19 cases. METHODS: Five cancer tissue samples from disparate tumor regions and one from normal lung were harvested at surgery. EBC was collected for DNA analysis the previous day. KRAS point mutations at codon 12 were detected using mutant-enriched PCR technique and pyrosequenced. RESULTS: Forty-six cancers revealed concordance of KRAS mutation status: 27 contained mutated KRAS and 19 had only wild KRAS. Five NSCLCs revealed inhomogeneous distribution of KRAS mutation. Two different mutations were found in 14 NSCLCs and the most frequent one was G12D and G12V (n = 8). No mutated KRAS was found in normal lung. The concordance ratios of KRAS sequence in codon 12 between EBC-DNA and cancer were 18/19 for NSCLC patients and 11/12 for KRAS mutation positive NSCLC. CONCLUSIONS: Intratumor heterogeneity and inhomogeneous distribution of KRAS point mutation in codon 12 in cancer tissue can occur in NSCLCs. There was a high accordance between KRAS mutation status in EBC-DNA and cancer tissue in NSCLC patients what suggests usefulness of monitoring KRAS mutation in EBC-DNA as a biomarker of NSCLC.

No impairment of pulmonary function in children with Henoch-Schonlein purpura after 4-year follow-up.

Henoch-Schonlein purpura (HSP) is a generalized form of IgA-mediated vasculitis that usually spares pulmonary circulation. Nevertheless, it is conceivable that subclinical changes at the HSP onset may lead to lung impairment in the long term. Therefore, we decided to follow a group of HSP patients for 4 years to monitor changes in pulmonary function. A group of 11 children and adolescents diagnosed with HSP without apparent pulmonary involvement was subjected to pulmonary function tests (PFTs), i.e., spirometry, body plethysmography, and diffusing capacity for CO (DLCO); these tests were repeated after 48 months. No significant impairment was observed in variables of spirometry, body plethysmography, and DLCO expressed as % of predicted values (% predicted) after 4 years. Specifically, no significant change in DLCO, corrected for blood hemoglobin concentration was noted, i.e., 79.3 ± 10.1 vs. 81.6 ± 14.7 % predicted at the beginning and the end of the study, respectively. IgA vasculitis seems to spare pulmonary circulation as we found no impairment in PFTs within the study time frame and a median of almost 6 years from the first episode of the disease.

No evidence of enhanced oxidant production in blood obtained from patients with obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is a recognized risk factor for cardiovascular morbidity and mortality, perhaps due to causative exacerbations of systemic oxidative stress. Putative oxidative stress related to numerous episodes of intermittent hypoxia, may be an oxidants chief driving force in OSAS patients. METHODS: We assessed the resting and n-formyl-methionyl-leucyl-phenylalanine (fMLP)- induced whole blood chemiluminescence (as a measure of oxidant production by polymorphonuclear leukocytes and monocytes), ferric reducing ability of plasma (FRAP) and H2O2 generation in the whole blood of 27 untreated OSAS patients, 22 subjects after a night of CPAP therapy and 11 controls without OSAS. All of them were matched to age, BMI (body mass index) and smoking habits. All parameters were measured before and after polysomnography-controlled sleep, individual results were obtained as a mean from duplicated experiments. RESULTS: No significant differences were distinguished between evening and morning blood chemiluminescence, H2O2 activity and FRAP within and between all three study groups.For instance patients with untreated OSAS had similar morning and evening resting whole blood chemiluminescence (2.3 +/- 2.2 vs. 2.4 +/- 2.2 [aU.10-4 phagocytes]), total light emission after stimulation with fMLP (1790 +/- 1371 vs. 1939 +/- 1532 [aU.s.10-4 phagocytes]), as well as FRAP after 3 min. plasma incubation (602 +/- 202 vs. 671 +/- 221 [uM]). Although, in the subgroup of 11 patients with severe OSAS (apnea/hypopnea index 58 +/- 18/h and oxygen desaturation index 55 +/- 19/h), the morning vs. evening resting chemiluminescence and total light emission after stimulation with fMLP observed a propensity to elevate 2.5 +/- 2.7 vs. 1.9 +/- 1.8 [aU.10-4 phagocytes] and 1778 +/- 1442 vs. 1503 +/- 1391 [aU.s.10-4 phagocytes], respectively, these did not attain statistical significance (p > 0.05). CONCLUSION: Our investigation exposed no evidence in the overproduction of oxidants via circulating phagocytes, once considered a culprit in the oxidative stress of OSAS patients.