Recent Advances in Natural Polyphenol Research

Polyphenols are secondary metabolites produced by plants, which contribute to the plant’s defense against abiotic stress conditions (e.g., UV radiation and precipitation), the aggression of herbivores, and plant pathogens. Epidemiological studies suggest that long-term consumption of plant polyphenols protects against cardiovascular disease, cancer, osteoporosis, diabetes, and neurodegenerative diseases. Their structural diversity has fascinated and confronted analytical chemists on how to carry out unambiguous identification, exhaustive recovery from plants and organic waste, and define their nutritional and biological potential. The food, cosmetic, and pharmaceutical industries employ polyphenols from fruits and vegetables to produce additives, additional foods, and supplements. In some cases, nanocarriers have been used to protect polyphenols during food processing, to solve the issues related to low water solubility, to transport them to the site of action, and improve their bioavailability. This review summarizes the structure-bioactivity relationships, processing parameters that impact polyphenol stability and bioavailability, the research progress in nanocarrier delivery, and the most innovative methodologies for the exhaustive recovery of polyphenols from plant and agri-waste material

cΔlog kwIAM: can we afford estimation of small molecules’ blood-brain barrier passage based upon in silico phospholipophilicity?

56 compounds, whose log BB values were known from the scientific literature, were considered and their phospholipophilicity values were calculated in silico. These values, along with either experimentally determined or calculated lipophilicity values, were used to extract c?/?'log k w IAM parameters. c?/?'log k w IAM values were found inversely related to data of blood-brain barrier passage, especially in the <-0.20 log BB range and on the IAM.PC.DD2 phase (r 2 = 0.79). In multiple linear regression, satisfactory statistic models (r 2 (n-1) = 0.76), based on c?/?'log k w IAM.MG along with other in silico calculated descriptors, were achieved. This method brings the potential to be applied, along with other methodologies, to filter out solutes whose BBB permeation is foreseen to be substandard, thus allowing pharmaceutical companies/research institutes to focus on candidates that are more likely to concentrate in the brain

Comprehensive two-dimensional liquid chromatography as a biomimetic screening platform for pharmacokinetic profiling of compound libraries in early drug development

A comprehensive two-dimensional liquid chromatography-based biomimetic platform (LCxLC) has been developed and validated for drug diffusion studies. Human serum albumin (HSA) and immobilized artificial membrane (IAM) were thereby used in the first (1D) and second (2D) separation dimension, respectively. While the former was meant to emulate the blood, the latter was instead intended to mimic the intestinal mucosa epithelium. Therefore, the experimental conditions, i.e. pH, temperature and buffer composition, were modulated to reflect faithfully in vivo conditions. 30 compounds, whose effective intestinal permeability (Peff) assayed in situ on humans by a validated technique was known from the literature, were used as model drugs.A good and orthogonal separation was achieved for the whole dataset, although for a better distribution of the most polar compounds in the elution window a segmented gradient elution program had to be employed. Interestingly, the passively uptaken compounds having the most favourable Peff populated a specific area of the 2D plots, implying that the affinity for HSA and IAM has to lie in specific ranges in order for a compound to be satisfactorily absorbed from the intestinal lumen.Although these results should be regarded as preliminary, this work paves an entirely new and unprecedented way to profile pharmaceutically relevant compounds for their in vivo absorption and distribution potential

Synergism between bisphenol a exposure and overweight/obesity in increasing the malignancy risk in a cohort of patients with thyroid nodules

BPA exposure conferred higher risk of thyroid cancer only in case of concomitant overweight/obesity, therefore suggesting a synergistic action between BPA and the excess of adipose tissue in promoting thyroid carcinogenesis

Tracking Down of a Selected Panel of Parabens: A Validated Method to Evaluate Their Occurrence in Skin Layers

A method was set up and validated to identify and quantify seven parabens in each of the three skin layers, i.e., Stratum Corneum, Epidermis, and Dermis, because, even if only some analogues are legally allowed in Europe, forbidden parabens are also detected in many personal care products and therefore can be absorbed by the skin. A solid/liquid extraction followed by a gradient elution chromatographic separation method was performed and validated according to European guidelines. Our validated method afforded the detection of all seven parabens with limit of detection values ranging from 0.026 to 0.090 μg mL−1 and recoveries ranging from 61.80 to 105.73 μg mL−1 at high and low concentration values (50.0–5.0 μg mL−1), respectively. The proposed method can help assess paraben’s skin bioaccumulation since people are repeatedly exposed to consumer goods containing parabens in their daily routine, posing a chronic risk to human health

Evidence That p-Cresol and IL-6 Are Adsorbed by the HFR Cartridge: Towards a New Strategy to Decrease Systemic Inflammation in Dialyzed Patients?

Introduction Hemodialysis (HD) and hemodiafiltration clear only with a low efficiency the plasma from interleukin-6 and p-cresol, two protein-bound uremic toxins associated with high cardiovascular risk in end stage renal disease. HFR Supra is a double-chamber hemodiafiltration system in which the ultrafiltrate returns to the patient after its regeneration through a resin cartridge that binds hydrophobic and protein-bound solutes. In the present study, we evaluated whether the HFR cartridge can also bind total p-cresol and IL-6 and remove them from the ultrafiltrate. Methods We compared the levels of IL-6 and p-cresol in ultrafiltrate samples collected at the inlet (UFin) and at the outlet (UFout) of the cartridge at the start or at the end of a 240 min HFR session in 12 inflamed chronic HD patients. The pro-inflammatory activity of the ultrafiltrate samples was also determined by evaluating the changes that they induced in IL-6 mRNA expression and protein release in peripheral blood mononuclear cells from 12 healthy volunteers. IL-6 and p-cresol circulating levels were also assessed in peripheral plasma blood samples collected before and after HFR and, for comparison, a control HD. Results p-Cresol and IL-6 were lower in UFout than in UFin both at the start and at the end of the HFR session, suggesting that they were retained by the cartridge. IL-6 mRNA expression and release were lower in PBMC incubated with UFout collected at the end than with UFin collected at the start of HFR, suggesting that passage through the cartridge reduced UF pro-inflammatory activity. Plasma total p-cresol decreased by about 53% after HFR, and 37% after HD. IL-6 circulating values were unmodified by either these dialysis procedures. Conclusions This study shows that the HFR-Supra cartridge retains total p-cresol and IL-6 in the ultrafiltrate and lowers plasma total p cresol but not IL-6 levels. Trial Registration ClinicalTrials.gov NCT0186577

An Extract from Ficus carica Cell Cultures Works as an Anti-Stress Ingredient for the Skin

Psychological stress activates catecholamine production, determines oxidation processes, and alters the lipid barrier functions in the skin. Scientific evidence associated with the detoxifying effect of fruits and vegetables, the growing awareness of the long-term issues related to the use of chemical-filled cosmetics, the aging of the population, and the increase in living standards are the factors responsible for the growth of food-derived ingredients in the cosmetics market. A Ficus carica cell suspension culture extract (FcHEx) was tested in vitro (on keratinocytes cells) and in vivo to evaluate its ability to manage the stress-hormone-induced damage in skin. The FcHEx reduced the epinephrine (−43% and −24% at the concentrations of 0.002% and 0.006%, respectively), interleukin 6 (−38% and −36% at the concentrations of 0.002% and 0.006%, respectively), lipid peroxide (−25%), and protein carbonylation (−50%) productions; FcHEx also induced ceramide synthesis (+150%) and ameliorated the lipid barrier performance. The in vivo experiments confirmed the in vitro test results. Transepidermal water loss (TEWL; −12.2%), sebum flow (−46.6% after two weeks and −73.8% after four weeks; on the forehead −56.4% after two weeks and −80.1% after four weeks), and skin lightness (+1.9% after two weeks and +2.7% after four weeks) defined the extract’s effects on the skin barrier. The extract of the Ficus carica cell suspension cultures reduced the transepidermal water loss, the sebum production, the desquamation, and facial skin turning to a pale color from acute stress, suggesting its role as an ingredient to fight the signs of psychological stress in the skin

Parabens Permeation through Biological Membranes: A Comparative Study Using Franz Cell Diffusion System and Biomimetic Liquid Chromatography

Parabens (PBs) are used as preservatives to extend the shelf life of various foodstuffs, and pharmaceutical and cosmetic preparations. In this work, the membrane barrier passage potential of a subset of seven parabens, i.e., methyl-, ethyl-, propyl- isopropyl, butyl, isobutyl, and benzyl paraben, along with their parent compound, p-hydroxy benzoic acid, were studied. Thus, the Franz cell diffusion (FDC) method, biomimetic liquid chromatography (BLC), and in silico prediction were performed to evaluate the soundness of both describing their permeation through the skin. While BLC allowed the achievement of a full scale of affinity for membrane phospholipids of the PBs under research, the permeation of parabens through Franz diffusion cells having a carbon chain > ethyl could not be measured in a fully aqueous medium, i.e., permeation enhancer-free conditions. Our results support that BLC and in silico prediction alone can occasionally be misleading in the permeability potential assessment of these preservatives, emphasizing the need for a multi-technique and integrated experimental approach

Plasma p-Cresol Lowering Effect of Sevelamer in Peritoneal Dialysis Patients: Evidence from a Cross-Sectional Observational Study.

p-Cresol is a by-product of the metabolism of aromatic aminoacid operated by resident intestinal bacteria. In patients with chronic kidney disease, the accumulation of p-cresol and of its metabolite p-cresyl-sulphate, that represents more than 95% of circulating p-cresol, causes endothelial dysfunction and ultimately increases the cardiovascular risk of these patients. Therapeutic strategies able to reduce plasma p-cresol levels are highly demanded but unfortunately not available yet. Because it has been reported that the phosphate binder sevelamer also sequesters p-cresol in vitro we hypothesized that it could do so also in peritoneal dialysis patients. To explore this hypothesis we measured total cresol plasma concentrations in 57 patients with end-stage renal disease on peritoneal dialysis patients, 29 receiving sevelamer for the treatment of hyperphosphatemia and 28 patients not assuming this drug. Among the patients not assuming sevelamer, 16 were treated with lanthanum whereas the remaining 12 received no drug because they were not hyperphosphatemic. When we compared total p-cresol plasma concentrations in these different groups of patients, we, we found that plasma p-cresol levels were significantly lower in patients receiving sevelamer than in subjects receiving lanthanum or no drug. Patients assuming sevelamer had also lower high sensitivity C-reactive protein serum concentrations compared to patients not assuming this drug. Multiple linear regression analysis showed that Conversely, no difference either in residual glomerular filtration rate, total weekly dialysis dose or serum phosphate levels were observed among the different groups. These results suggest that sevelamer could be an effective strategy to lower p-cresol circulating levels in peritoneal dialysis patients in which it could also favorably affect the cardiovascular risk because of its anti-inflammatory effect

Into the toxicity potential of an array of parabens by biomimetic liquid chromatography, cell viability assessments and in silico predictions

Five parabens (PBs) i.e., Methylparaben (MP), Ethylparaben (EP), Isopropylparaben (iPrP), Isobutylparaben (iBuP), Benzylparaben (BzP), and their parent compound i.e., para–hydroxy Benzoic Acid (pHBA), were studied both in vitro and in silico. Specifically, we determined their retention on several both protein- (Human Serum Albumin and α1-acidic glycoprotein) and lipid- (immobilized artificial membrane (IAM)) based biomimetic stationary phases to evaluate their penetration potential through the biomembranes and their possible distribution in the body. The IAM phases were based either on phosphatidylcholine (PC) analogues i.e., PC.MG and PC.DD2 or on sphingomyelin (SPH). We also assessed their viability effect on breast cancer cells (MCF-7) via MTT assay subjecting the cells to five different PB concentrations i.e., 100 μM, 10 μM, 1 μM, 0.1 μM and 0.01 μM. Finally, their pharmacokinetics, and toxicity were assessed by the ADMET Predictor™ software.Isopropylparaben was found to be more active than 17β estradiol (E2) employed as positive control, on the screened cell line inducing cell proliferation up to 150 % more of untreated cells. Other analogues showed only a slight/moderate cell proliferation activity, with parabens having longer/branched side chain showing, on average, a higher proliferation rate. Significant linear direct relationships (for PC.DD2 r2 = 0.89, q2 = 0.86, for SPH r2 = 0.89, q2 = 0.85, for both P value < 0.05) were observed between the difference in proliferative effect between the readout and the control at 0.01 μM concentration and the retention on the IAM phases measured at pH 5.0 for all compounds but pHBA, which is the only analyte of the dataset supporting a carboxylic acid moiety. IAM affinity data measured at pH 7.0 were found to be related to the effective human jejunal permeability as predicted by the software ADMET® Predictor, which is relevant when PBs are added to pharmaceutical and food commodities