In Vitro Bioaccessibility and Anti-Inflammatory Activity of a Chemically Characterized Allium cepa L. Extract Rich in Quercetin Derivatives Optimized by the Design of Experiments.

Allium cepa L. is a highly consumed garden crop rich in biologically active phenolic and organosulfur compounds. This study aimed to assess the in vitro bioaccessibility and anti-inflammatory effect of a chemically characterized A. cepa extract rich in quercetin and its derivatives. Different varieties of A. cepa were studied; based on the highest total phenolic content, the "Golden" variety was selected. Its extracts, obtained from the tunicate bulb, tunic, and bulb, were subjected to determination of quercetin and its derivatives with LC-MS analysis and based on the highest total quercetin content, the tunic extract was utilized for further experiments. The extraction method was optimized through a design of experiment (DoE) method via full factorial design, which showed that 40% ethanol and 1 g tunic/20 mL solvent are the best extraction conditions. HPLC analysis of the optimized tunic extract identified 14 flavonols, including 10 quercetin derivatives. As far as in vitro bioaccessibility was concerned, the increases in some quercetin derivatives following the gastro-duodenal digestion process support the bioaccessibility of these bioactive compounds. Moreover, the extract significantly inhibited the production of PGE2 in stimulated J774 cell lines, while no effects of the tunic extract were observed against the release of IL-1ß, TNF-α, and nitrites. The study provided insights into the optimized extraction conditions to obtain an A. cepa tunic extract rich in bioavailable quercetin derivatives with significant anti-inflammatory effects against PGE2.

Targeting epigenetics in cancer: therapeutic potential of flavonoids.

Irrespective of sex and age, cancer is the leading cause of mortality around the globe. Therapeutic incompliance, unwanted effects, and economic burdens imparted by cancer treatments, are primary health challenges. The heritable features in gene expression that are propagated through cell division and contribute to cellular identity without a change in DNA sequence are considered epigenetic characteristics and agents that could interfere with these features and are regarded as potential therapeutic targets. The genetic modification accounts for the recurrence and uncontrolled changes in the physiology of cancer cells. This review focuses on plant-derived flavonoids as a therapeutic tool for cancer, attributed to their ability for epigenetic regulation of cancer pathogenesis. The epigenetic mechanisms of various classes of flavonoids including flavonols, flavones, isoflavones, flavanones, flavan-3-ols, and anthocyanidins, such as cyanidin, delphinidin, and pelargonidin, are discussed. The outstanding results of preclinical studies encourage researchers to design several clinical trials on various flavonoids to ascertain their clinical strength in the treatment of different cancers. The results of such studies will define the clinical fate of these agents in future.

Gastrointestinal Disorders and Metabolic Syndrome: Dysbiosis as a Key Link and Common Bioactive Dietary Components Useful for their Treatment.

Gastrointestinal (GI) diseases, which include gastrointestinal reflux disease, gastric ulceration, inflammatory bowel disease, and other functional GI disorders, have become prevalent in a large part of the world population. Metabolic syndrome (MS) is cluster of disorders including obesity, hyperglycemia, hyperlipidemia, and hypertension, and is associated with high rate of morbidity and mortality. Gut dysbiosis is one of the contributing factors to the pathogenesis of both GI disorder and MS, and restoration of normal flora can provide a potential protective approach in both these conditions. Bioactive dietary components are known to play a significant role in the maintenance of health and wellness, as they have the potential to modify risk factors for a large number of serious disorders. Different classes of functional dietary components, such as dietary fibers, probiotics, prebiotics, polyunsaturated fatty acids, polyphenols, and spices, possess positive impacts on human health and can be useful as alternative treatments for GI disorders and metabolic dysregulation, as they can modify the risk factors associated with these pathologies. Their regular intake in sufficient amounts also aids in the restoration of normal intestinal flora, resulting in positive regulation of insulin signaling, metabolic pathways and immune responses, and reduction of low-grade chronic inflammation. This review is designed to focus on the health benefits of bioactive dietary components, with the aim of preventing the development or halting the progression of GI disorders and MS through an improvement of the most important risk factors including gut dysbiosis.

Hydromethanolic Extracts from Adansonia digitata L. Edible Parts Positively Modulate Pathophysiological Mechanisms Related to the Metabolic Syndrome.

Metabolic syndrome includes a cluster of risk factors for many pathological conditions, including hyperglycemia, abdominal obesity, hyperlipidemia, and hypertension. Adansonia digitata L. (also known as baobab) is used in traditional African Medicine and recent studies showed that it improves the metabolism of carbohydrates and lipids. The aim of this study is to investigate the mechanisms of action associated with the beneficial effects of extracts from the edible parts of baobab (fruit pulp, leaves, raw and toasted seeds), evaluating their inhibitory activity against: alpha-amylase, alpha-glucosidase, angiotensin-converting enzyme, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, and pancreatic lipase. Baobab fruit pulp and leaf extracts resulted to be the most active ones and were then tested on the differentiation process of SW-872 human liposarcoma cells to mature adipocytes. The addition of these latter extracts did not affect triglyceride accumulation, indicating a neutral impact on this parameter. The findings here reported help to explain the growing amount of evidence on the biological properties of baobab and provide suggestions about their use in food and nutraceutical fields.

Novel therapeutic strategies for stroke: The role of autophagy.

Autophagy is an important biological mechanism involved in the regulation of numerous fundamental cellular processes that are mainly associated with cellular growth and differentiation. Autophagic pathways are vital for maintaining cellular homeostasis by enhancing the turnover of nonfunctional proteins and organelles. Neuronal cells, like other eukaryotic cells, are dependent on autophagy for neuroprotection in response to stress, but can also induce cell death in cerebral ischemia. Recent studies have demonstrated that autophagy may induce neuroprotection following acute brain injury, including ischemic stroke. However in some special circumstances, activation of autophagy can induce cell death, playing a deleterious role in the etiology and progression of ischemic stroke. Currently, there are no therapeutic options against stroke that demonstrate efficient neuroprotective abilities. In the present work, we will review the significance of autophagy in the context of ischemic stroke by first outlining its role in ischemic neuronal death. We will also highlight the potential therapeutic applications of pharmacological modulators of autophagy, including some naturally occurring polyphenolic compounds that can target this catabolic process. Our findings provide renewed insight on the mechanism of action of autophagy in stroke together with potential neuroprotective compounds, which may partially exert their function through enhancing mitochondrial function and attenuating damaging autophagic processes.

Bioavailability and In Vivo Antioxidant Activity of a Standardized Polyphenol Mixture Extracted from Brown Propolis.

Several lines of evidence demonstrate the antioxidant, anti-inflammatory and antimicrobial activities of propolis, mostly ascribed to its polyphenol content. However, little is known regarding the bioavailability of propolis in acute and prolonged settings of oral administration. In this study, we first determined the content of the main polyphenols in a brown propolis extract obtained using a patented extraction method (Multi Dinamic Extraction-M.E.D.) by RP-HPLC-UV-PDA-MSn analysis, followed by the bioavailability of galangin and chrysin, the most abundant polyphenols in the mixture (7.8% and 7.5% respectively), following acute (single bolus of 500 mg/kg containing about 3.65 mg of the polyphenol mixture) and prolonged (100, 250 and 500 mg/kg body for 30 days) oral administration in 30 male 8 weeks old C57BL/6 wild-type mice. In the acute setting, blood was taken at 30 s and 5, 10, 15, 20, 25, 30, 45, 60 and 120 min following the oral bolus. In the prolonged setting, blood samples were obtained after 10, 20 or 30 days of administration. At the end of treatment, expression of antioxidant enzymes (superoxyde dismutase, SOD-1; catalase, CAT; glutathione peroxidase, GSS) was evaluated in liver tissue. Following both acute and prolonged administration, neither galangin nor chrysin were detectable in the plasma of mice, whereas the glucuronide metabolite of galangine was detectable 5 min after acute administration. At the end of the prolonged treatment SOD-1 was found to have increased significantly, unlike CAT and GSS. Overall, these data suggest that oral administration of whole brown propolis extract is followed by rapid absorption and metabolization of galangin followed by adaptations of the antioxidant first line defense system.

In vitro polyphenol effects on apoptosis: An update of literature data.

Polyphenols are secondary plant metabolites which have been studied extensively for their health-promoting properties, and which could also exert pharmacological activities ranging from anti-inflammatory effects, to cytotoxic activity against cancer cells. The main mechanism for programmed cell death is represented by apoptosis, and its dysregulation is involved in the etiopathology of cancer. As such, substances able to induce apoptosis in cancer cells could be used as new anticancer agents. The aim of this paper is to review literature data on the apoptotic effects of polyphenols and the molecular mechanisms through which they induce these effects in cancer cells. In addition, a brief summary of the new delivery forms used to increase the bioavailability, and clinical impact of polyphenols is provided. The studies reported show that many polyphenol rich plant extracts, originating from food and herbal medicine, as well as isolated polyphenols administered individually or in combination, can regulate cell apoptosis primarily through intrinsic and extrinsic mechanisms of action in in vitro conditions. Due to these promising results, the use of polyphenols in the treatment of cancer should therefore be deeply investigated. In particular, because of the low number of clinical trials, further studies are required to evaluate the anticancer activity of polyphenols in in vivo conditions.

Antimicrobial Potential of Curcumin: Therapeutic Potential and Challenges to Clinical Applications.

Curcumin is a bioactive compound that is extracted from Curcuma longa and that is known for its antimicrobial properties. Curcuminoids are the main constituents of curcumin that exhibit antioxidant properties. It has a broad spectrum of antibacterial actions against a wide range of bacteria, even those resistant to antibiotics. Curcumin has been shown to be effective against the microorganisms that are responsible for surgical infections and implant-related bone infections, primarily Staphylococcus aureus and Escherichia coli. The efficacy of curcumin against Helicobacter pylori and Mycobacterium tuberculosis, alone or in combination with other classic antibiotics, is one of its most promising antibacterial effects. Curcumin is known to have antifungal action against numerous fungi that are responsible for a variety of infections, including dermatophytosis. Candidemia and candidiasis caused by Candida species have also been reported to be treated using curcumin. Life-threatening diseases and infections caused by viruses can be counteracted by curcumin, recognizing its antiviral potential. In combination therapy with other phytochemicals, curcumin shows synergistic effects, and this approach appears to be suitable for the eradication of antibiotic-resistant microbes and promising for achieving co-loaded antimicrobial pro-regenerative coatings for orthopedic implant biomaterials. Poor water solubility, low bioavailability, and rapid degradation are the main disadvantages of curcumin. The use of nanotechnologies for the delivery of curcumin could increase the prospects for its clinical application, mainly in orthopedics and other surgical scenarios. Curcumin-loaded nanoparticles revealed antimicrobial properties against S. aureus in periprosthetic joint infections.

Long-Aged Parmigiano Reggiano PDO: Trace Element Determination Targeted to Health.

The concentrations of four health-related trace elements were measured using Atomic Absorption Spectroscopy in long-ripened (24- and 40-months) Parmigiano Reggiano (PR) PDO cheese, obtained from both summer and winter milk. To date, there are limited data on PR trace element concentrations, and no data about long-ripened cheese, especially when ripened for 40 months. Thus, the aim of this investigation is to determine chromium, manganese, selenium, and zinc concentrations, improving the available data on these trace elements and increasing knowledge of the biological properties of PR linked to their content in this cheese. The results show that 40-month ripened PR is a source of selenium and chromium, according to definitions under the European Regulation 1924/2006, as a 30 g cheese portion contains 11 ± 2 µg (summer milk) and 10 ± 1 µg (winter milk) of selenium and 8 ± 1 µg (summer and winter milk) of chromium, providing in excess of 8.25 and 6 µg per portion, respectively. This represents 15% of nutrient reference intake values for adults. These findings allow for the claim to be made that PR possesses the health properties ascribed to food sources of selenium and chromium according to European Regulation 432/2012.

Spice-Derived Bioactive Compounds Confer Colorectal Cancer Prevention via Modulation of Gut Microbiota.

Colorectal cancer (CRC) is the second most frequent cause of cancer-related mortality among all types of malignancies. Sedentary lifestyles, obesity, smoking, red and processed meat, low-fiber diets, inflammatory bowel disease, and gut dysbiosis are the most important risk factors associated with CRC pathogenesis. Alterations in gut microbiota are positively correlated with colorectal carcinogenesis, as these can dysregulate the immune response, alter the gut's metabolic profile, modify the molecular processes in colonocytes, and initiate mutagenesis. Changes in the daily diet, and the addition of plant-based nutraceuticals, have the ability to modulate the composition and functionality of the gut microbiota, maintaining gut homeostasis and regulating host immune and inflammatory responses. Spices are one of the fundamental components of the human diet that are used for their bioactive properties (i.e., antimicrobial, antioxidant, and anti-inflammatory effects) and these exert beneficial effects on health, improving digestion and showing anti-inflammatory, immunomodulatory, and glucose- and cholesterol-lowering activities, as well as possessing properties that affect cognition and mood. The anti-inflammatory and immunomodulatory properties of spices could be useful in the prevention of various types of cancers that affect the digestive system. This review is designed to summarize the reciprocal interactions between dietary spices and the gut microbiota, and highlight the impact of dietary spices and their bioactive compounds on colorectal carcinogenesis by targeting the gut microbiota.

Hydroethanolic Extract of Prunus domestica L.: Metabolite Profiling and In Vitro Modulation of Molecular Mechanisms Associated to Cardiometabolic Diseases.

High consumption of fruit and vegetables has an inverse association with cardiometabolic risk factors. This study aimed to chemically characterize the hydroethanolic extract of P. domestica subsp. syriaca fruit pulp and evaluate its inhibitory activity against metabolic enzymes and production of proinflammatory mediators. Ultra-high-performance liquid chromatography high-resolution mass spectrometry(UHPLC-HRMS) analysis showed the presence of hydroxycinnamic acids, flavanols, and glycoside flavonols, while nuclear magnetic resonance(NMR) analysis showed, among saccharides, an abundant presence of glucose. P. domestica fruit extract inhibited α-amylase, α-glucosidase, pancreatic lipase, and HMG CoA reductase enzyme activities, with IC50 values of 7.01 mg/mL, 6.4 mg/mL, 6.0 mg/mL, and 2.5 mg/mL, respectively. P. domestica fruit extract inhibited lipopolysaccharide-induced production of nitrite, interleukin-1 ß and PGE2 in activated J774 macrophages. The findings of the present study indicate that P. domestica fruit extracts positively modulate in vitro a series of molecular mechanisms involved in the pathophysiology of cardiometabolic diseases. Further research is necessary to better characterize these properties and their potential application for human health.

Beneficial Effects of Plant Extracts and Bioactive Food Components in Childhood Supplementation.

The pivotal role of childhood nutrition has always roused a growing interest from the scientific community. Plant extracts and bioactive dietary components play a significant role in the maintenance of human health and wellness, with the potential to modulate risk factors and manage symptoms for a large number of common childhood disorders such as memory impairment, respiratory illnesses, gastrointestinal disorders, metabolic derangements, and pathologies related to the oral cavity. This review is designed to highlight the health benefits of botanical extracts and bioactive dietary components in children as evidenced by clinical trials, considering their safety with regards to childhood sensibilities. The supplementation of children with the herbal extracts or bioactive components mentioned in this review leads to the conclusion that they are useful for treating various ailments, with no serious adverse events being reported. However, for the limited number of investigations specifically focused on the safety of such products in children, time is needed to expand the literature data covering the safety of childhood supplementation with botanical extract and bioactive food components.

Safety and efficacy of alpha-lipoic acid oral supplementation in the reduction of pain with unknown etiology: A monocentric, randomized, double-blind, placebo-controlled clinical trial.

INTRODUCTION: Extensive evidence suggests that alpha-lipoic acid (ALA) is effective in diabetic neuropathy pain management. However, little is known on its safety and efficacy in reducing idiopathic pain in normoglycemic subjects. The aim of this study was to evaluate ALA food supplement safety and efficacy in the reduction of different forms of idiopathic pain. METHODS: Two-hundred and ten normoglycemic adults suffering from idiopathic pain (i.e. 57 subjects with primitive neuropathic pain, 141 subjects with arthralgia with unknown etiology, and 12 subjects with idiopathic myalgia) were randomized to receive placebo, 400 mg/day, or 800 mg/day of ALA. Participants underwent two visits (at baseline = t0, and after 2 months = t1) in which two validated questionaries for pain (numerical rating scale [NRS] and visual analogue scale [VAS]) were collected; fasting blood glucose assessment, adverse effects, and renal and hepatic toxicity were also monitored. RESULTS: At t1, none of subjects treated with ALA reported a decreased glycemia or adverse effects. The treated subjects showed a significant reduction in NRS (p < 0.001) while the placebo group did not show any NRS reduction (p = 0.86). Similar results were also obtained for VAS. Statistical analysis aimed at detecting possible differences in NRS and VAS scores among treatment groups based on the source of pain did not reveal any significant effect. CONCLUSIONS: Since the management of idiopathic pain is challenging for physicians, the use of ALA food supplements could be a feasible option, based on its safety and efficacy compared to commonly-used analgesic drugs.

In vivo bioavailability and in vitro toxicological evaluation of the new butyric acid releaser N-(1-carbamoyl-2-phenyl-ethyl) butyramide.

A large body of evidence suggests that supplementation of butyric acid exerts beneficial intestinal and extra-intestinal effects. Unfortunately, unpleasant sensorial properties and unfavourable physico-chemical properties strongly limit its use in food supplements and foods for medicinal purposes. N-(1-carbamoyl-2-phenyl-ethyl) butyramide (FBA) is a new butyric acid releaser in solid form with neutral sensorial properties. The aim of this investigation is to provide preliminary information on its pharmacokinetic and toxicological properties through the study of a) in vivo bioavailability of FBA administered by oral gavage to male and female Swiss CD1 mice in comparison with sodium butyrate, b) the influence of digestion on FBA stability through an in vitro simulated oro-gastro-duodenal digestion process, and c) in vitro toxicological profile by means of the Ames Test and Micronucleus Test. The results reveal that FBA is a good butyric acid releaser, being able to increase butyrate serum concentration in a dose and time dependent manner in both male and female mice with a pharmacokinetic profile similar to that obtained from sodium butyrate as such. These data are confirmed by investigating the influence of digestion on FBA, which undergoes extensive hydrolysis following oro-gastro-duodenal digestion, especially in duodenal conditions, with a residual concentration of less than 10% of the initial FBA concentration. Finally, in the Ames and Micronucleus Tests, FBA does not show any in vitro genotoxicity as it is non mutagenic in the Ames Test and results to be unable to induce chromosome breaks in the Micronucleus Test. In conclusion, FBA is a new butyric acid releaser that can overcome the disadvantages of butyric acid while maintaining the same pharmacokinetic properties and safety profile, as shown by the results of the preliminary in vitro toxicological studies performed in this investigation.

Metabolic profiling, in vitro bioaccessibility and in vivo bioavailability of a commercial bioactive Epilobium angustifolium L. extract.

The global diffusion of benign prostatic hyperplasia (BPH) demands the search for safe and effective treatment alternatives to the drugs commonly used, which exert both side and adverse effects. Among plant-based products, the extracts of Epilobium angustifolium L. (EAEs) could improve BPH symptoms thanks to the presence of ellagitannins and their anti-inflammatory metabolites, urolithins. This study focused its attention on a commercial EAE, standardized to contain ≥ 15 % oenothein B, to determine a) the metabolic profile and the chemical degradation induced by digestion, b) in vivo bioavailability after acute and prolonged treatments of CD1 mice, and c) in vitro antioxidant activity. Utilizing RP-HPLC-PDA-ESI-MSn analysis, 20 different compounds were identified. Polyphenols suffered from degradation after both orogastric and duodenal digestion processes, suggesting that gastro-resistant coating agents are required to preserve the bioactive components occurring in the EAE phytocomplex from orogastric digestion. In vivo data underlined the presence of urolithins only after the prolonged treatment, confirming that the gut fermentation process requires at least 24 h to produce urolithins. Finally, an increase of Superoxide Dismutase-1 (SOD-1), which represents one of the fundamental endogenous antioxidant defenses, was determined in an EAE pretreated LNCap cell model system, confirming EAE antioxidant activity.

Cardioprotective Effects of Taurisolo® in Cardiomyoblast H9c2 Cells under High-Glucose and Trimethylamine N-Oxide Treatment via De Novo Sphingolipid Synthesis.

In addition to high plasma glucose, increased levels of trimethylamine N-oxide (TMAO) have been found in obese subjects, where are considered as a novel risk factor for cardiovascular diseases. The present study aimed to investigate the effect of a novel nutraceutical formulation based on grape polyphenols (registered as Taurisolo®) in counteracting TMAO- and high glucose (HG)-induced cytotoxicity in cardiomyoblast H9c2 cells. Cell damage was induced with HG (HG-H9c2) and HG+TMAO (THG-H9c2); both experimental cell models were, thus, incubated for 72 h in the presence or absence of Taurisolo®. It was observed that Taurisolo® significantly increased the cell viability and reduced lactate dehydrogenase and aspartate transaminase release in both HG- and THG-H9c2 cells. Additionally, through its antioxidant activity, Taurisolo® modulated cell proliferation via ERK activation in THG-H9c2. Furthermore, Taurisolo® was able to induce autophagic process via increasing the expression of LC3II, a protein marker involved in formation of autophagosome and ex novo synthesis of sphingomyelin, ceramides, and their metabolites both in HG- and THG-H9c2 cells. Finally, Taurisolo® reduced hypertrophy and induced differentiation of HG-H9C2 cells into cardiomyocyte-like cells. These data suggest that Taurisolo® counteracts the toxicity induced by TMAO and HG concentrations increasing autophagic process and activating de novo sphingolipid synthesis, resulting in a morphological cell remodeling. In conclusion, our results allow speculating that Taurisolo®, combined with energy restriction, may represent a useful nutraceutical approach for prevention of cardiomyopathy in obese subjects.

Modulation of Keap1/Nrf2/ARE Signaling Pathway by Curcuma- and Garlic-Derived Hybrids.

Nrf2 is a basic leucine zipper transcription factor that binds to the promoter region of the antioxidant response element (ARE), inducing the coordinated up-regulation of antioxidant and detoxification genes. We recently synthesized a set of new molecules by combining the functional moieties of curcumin and diallyl sulfide, both known to induce the expression of antioxidant phase II enzymes by activating Nrf2 pathway. The aim of the study is to investigate the ability of such compounds to activate Keap1/Nrf2/ARE cytoprotective pathway, in comparison with two reference Nrf2-activators: curcumin and dimethyl fumarate, a drug approved for the treatment of relapsing-remitting multiple sclerosis. Furthermore, since Nrf2 pathway is known to be regulated also by epigenetic modifications, including key modifications in microRNA (miRNA) expression, the effects of the hybrids on the expression levels of selected miRNAs, associated with Nrf2 signaling pathway have also been investigated. The results show that compounds exert antioxidant effect by activating Nrf2 signaling pathway and inducing the ARE-regulated expression of its downstream target genes, such as HO-1 and NQO1, with two hybrids to a higher extent than curcumin. In addition, some molecules induce changes in the expression levels of miR-125b-5p, even if to a lesser extent than curcumin. However, no changes have been observed in the expression levels of mRNA coding for glutathione synthetase, suggesting that the modulation of this mRNA is not strictly under the control of miR-125b-5p, which could be influenced by other miRNAs.