Nifuroxazide-loaded cubosomes exhibit an advancement in pulmonary delivery and attenuate bleomycin-induced lung fibrosis by regulating the STAT3 and NF-κB signaling: A new challenge for unmet therapeutic needs.

Pulmonary fibrosis (PF) is a chronic progressive disease that portends a very poor prognosis. It has been suggested that STAT3 is a potential target in PF. This study highlights the importance of cubosomes as a drug delivery system in enhancing the bioavailability of nifuroxazide (NXZD), a poorly soluble STAT3 inhibitor. NXZD-loaded cubosomes (NXZD-LC) were in vitro and in vivo evaluated. In vitro, cubosomes presented a poly-angular nanosized particles with a mean size and zeta potential of 223.73 ± 4.73 nm and - 20.93 ± 2.38 mV, respectively. The entrapment efficiency of nifuroxazide was 90.56 ± 4.25%. The in vivo pharmacokinetic study and the lung tissue accumulation of NXZD were performed by liquid chromatography-tandem mass spectrometry after oral administration to rats. The nanoparticles exhibited a two-fold increase and 1.33 times of bioavailability and lung tissue concentration of NXZD compared to NXZD dispersion, respectively. In view of this, NXZD-LC effectively attenuated PF by targeting STAT3 and NF-κB signals. As a result, NXZD-LC showed a potential anti-inflammatory effect as revealed by the significant decrease in MCP-1, ICAM-1, IL-6, and TNF-α and suppressed fibrogenic mediators as indicated by the significant reduction in TGF-ß, TIMP-1, and PDGF-BB in lung tissues. Besides, NXZD-LC improved antioxidant defense mechanisms and decreased LDH and BALF total protein. These effects contributed to decreased collagen deposition. To conclude, cubosomes represent an advantageous pharmaceutical delivery system for enhancing pulmonary delivery of poorly soluble drugs. Additionally, repurposing NXZD as an antifibrotic agent is a promising challenge and new therapeutic approach for unmet therapeutic needs.

Preclinical Pharmacokinetics and Acute Toxicity in Rats of 5-{[(2E)-3-Bromo-3-carboxyprop-2-enoyl]amino}-2-hydroxybenzoic Acid: A Novel 5-Aminosalicylic Acid Derivative with Potent Anti-Inflammatory Activity.

Compound 5-{[(2E)-3-bromo-3-carboxyprop-2-enoyl]amino}-2-hydroxybenzoic acid (C1), a new 5-aminosalicylic acid (5-ASA) derivative, has proven to be an antioxidant in vitro and an anti-inflammatory agent in mice. The in vivo inhibition of myeloperoxidase was comparable to that of indomethacin. The aim of this study was to take another step in the preclinical evaluation of C1 by examining acute toxicity with the up-and-down OECD method and pharmacokinetic profiles by administration of the compound to Wistar rats through intravenous (i.v.), oral (p.o.), and intraperitoneal (i.p.) routes. According to the Globally Harmonized System, C1 belongs to categories 4 and 5 for the i.p. and p.o. routes, respectively. An RP-HPLC method for C1 quantification in plasma was successfully validated. Regarding the pharmacokinetic profile, the elimination half-life was approximately 0.9 h with a clearance of 24 mL/min after i.v. administration of C1 (50 mg/kg). After p.o. administration (50 mg/kg), the maximum plasma concentration was reached at 33 min, the oral bioavailability was about 77%, and the compound was amply distributed to all tissues evaluated. Therefore, C1 administered p.o. in rats is suitable for reaching the colon where it can exert its effect, suggesting an important advantage over 5-ASA and indomethacin in treating ulcerative colitis and Crohn's disease.

Graphene Oxide Loaded with Protocatechuic Acid and Chlorogenic Acid Dual Drug Nanodelivery System for Human Hepatocellular Carcinoma Therapeutic Application.

Hepatocellular carcinoma or hepatoma is a primary malignant neoplasm that responsible for 75-90% of all liver cancer in humans. Nanotechnology introduced the dual drug nanodelivery method as one of the initiatives in nanomedicine for cancer therapy. Graphene oxide (GO) loaded with protocatechuic acid (PCA) and chlorogenic acid (CA) have shown some anticancer activities in both passive and active targeting. The physicochemical characterizations for nanocomposites were conducted. Cell cytotoxicity assay and lactate dehydrogenase were conducted to estimate cell cytotoxicity and the severity of cell damage. Next, nanocomposite intracellular drug uptake was analyzed using a transmission electron microscope. The accumulation and localization of fluorescent-labelled nanocomposite in the human hepatocellular carcinoma (HepG2) cells were analyzed using a fluorescent microscope. Subsequently, Annexin V- fluorescein isothiocyanate (FITC)/propidium iodide analysis showed that nanocomposites induced late apoptosis in HepG2 cells. Cell cycle arrest was ascertained at the G2/M phase. There was the depolarization of mitochondrial membrane potential and an upregulation of reactive oxygen species when HepG2 cells were induced by nanocomposites. In conclusion, HepG2 cells treated with a graphene oxide-polyethylene glycol (GOP)-PCA/CA-FA dual drug nanocomposite exhibited significant anticancer activities with less toxicity compared to pristine protocatechuic acid, chlorogenic acid and GOP-PCA/CA nanocomposite, may be due to the utilization of a folic acid-targeting nanodrug delivery system.

Pharmacokinetics of gallic acid and protocatechuic acid in humans after dosing with Relinqing (RLQ) and the potential for RLQ-perpetrated drug-drug interactions on organic anion transporter (OAT) 1/3.

CONTEXT: Relinqing granules (RLQ) are being used alone or in combination with antibacterial drugs to treat urological disorders. OBJECTIVE: This study investigates the pharmacokinetics of RLQ in humans and the potential for RLQ-perpetrated interactions on transporters. MATERIALS AND METHODS: Twelve healthy subjects (six women and six men) participated to compare single- and multiple-dose pharmacokinetics of RLQ. In the single-dose study, all 12 subjects received 8 g of RLQ orally. After a 7-d washout period, the subjects received 8 g of RLQ for seven consecutive days (t.i.d.) and then a single dose. Gallic acid (GA) and protocatechuic acid (PCA) in plasma and urine samples were analysed using LC-MS/MS. The transfected cells were used to study the inhibitory effect of GA (50-5000 µg/L) and PCA (10-1000 µg/L) on transporters OAT1, OAT3, OCT2, OATP1B1, P-gp and BCRP. RESULTS: GA and PCA were absorbed into the blood within 1 h after administration and rapidly eliminated with a half-life of less than 2 h. The mean peak concentrations of GA (102 and 176 µg/L) and PCA (4.54 and 7.58 µg/L) were lower in males than females, respectively. The 24 h urine recovery rates of GA and PCA were about 10% and 5%, respectively. The steady-state was reached in 7 d without accumulation. GA was a potent inhibitor of OAT1 (IC50 = 3.73 µM) and OAT3 (IC50 = 29.41 µM), but not OCT2, OATP1B1, P-gp or BCRP. DISCUSSION AND CONCLUSIONS: GA and PCA are recommended as PK-markers in RLQ-related pharmacokinetic and drug interaction studies. We should pay more attention to the potential for RLQ-perpetrated interactions on transporters.

Potential bioaccessibility of phenolic acids in whole wheat products during in vitro gastrointestinal digestion and probiotic fermentation.

Health benefits of whole wheat products are partially attributed by their unique phenolic compounds. This study investigated effect of simulated gastrointestinal digestion and probiotic fermentation on releasing of phenolic acids from whole wheat foods (bread, cookie, and pasta). Kinetics results showed that more phenolic acids were released within the first hour of gastric and intestinal digestions compared to the prolonged digestion. Lactobacillus rhamnosus GG, a common probiotic strain, released additional phenolic acids from the digestive residues during fermentation. Simulated digestion released more soluble trans-ferulic acid than chemical extraction in breads (17.69 to 102.71 µg/g), cookie (15.81 to 54.43 µg/g), and pasta (4.88 to 28.39 µg/g). Phenolic acid composition of whole wheat products appeared to be better estimated by digestion methods than the chemical extraction method. The unique insoluble-bound nature and fermentability of wheat phenolic acids may lead to a mechanistic understanding of whole grain consumption for potential colorectal cancer prevention.

Bioaccessibility and antioxidant activity of phenolic acids, flavonoids, and anthocyanins of encapsulated Thai rice bran extracts during in vitro gastrointestinal digestion.

Encapsulation technique was applied to improve the stability of bioactive compounds in bran extracts from Thai rice cultivars (Khao Dawk Mali 105, Kiaw Ngu, Hom Nil, and Leum Pua), using three carriers including gelatin, gum Arabic, and the mixture of gelatin and gum Arabic. The microcapsules obtained using gelatin provided a higher production yield of 76.08, 85.63, 85.63 and 85.59%, respectively. A greater encapsulation efficiency was also observed in the extracts encapsulated with gelatin (93.45, 95.91, 91.19 and 95.09%, respectively). After simulated gastric and intestinal digestion, the microcapsules formed by using gelatin exhibited the higher release of bioactive compounds and antioxidant activity than unencapsulated extracts. However, the extracts encapsulated using gelatin and gum Arabic complex yielded the lowest release of bioactive compounds and their antioxidant activity after simulated digestion. The overall results showed that gelatin was an appropriate carrier that could protect bioactive compounds from the digestion conditions.

Bioaccessibility of phenolic acids in Canadian hulless barley varieties.

In order to gain understanding of bioaccessibility of phenolic acids in food-grade barley, an investigation was conducted using four cooked whole-grain, hulless, barley varieties. An in vitro digestion model was used to mimic human upper gastrointestinal digestion. Boiling enhanced the extractability of bound phenolic acids while digestion increased the level of free phenolic acids. The high bioaccessibilities observed were likely due to the release of bound phenolic acids during cooking and digestion. The major bioaccessible phenolics were ferulic and p-coumaric acids with bioaccessibility ranging from 131 to 173% and 51-135%, respectively. Peru-35 had significantly greater bioaccessibility of ferulic acid compared to other varieties. A hydroxycinnamic acid amide not reported before in boiled barley, N1, N8- dicaffeoyl spermidine, was identified in free phenolic extracts with relatively high abundance compared to the phenolic acids. It may provide additional anti-inflammatory and antioxidant functions. These cooked whole-grain, hulless barley varieties are sources of bioaccessible phenolic acids.

Polyphenols and Human Health: The Role of Bioavailability.

Polyphenols are a group of phytochemicals with potential health-promoting effects. They are classified as flavonoid (flavonols, flavanols, flavones, flavanones, isoflavones, and anthocyanins) and non-flavonoid molecules (phenolic acids, hydroxycinnamic acids, lignans, stilbenes, and tannins). Although an increasing number of trials have shown a correlation among polyphenol consumption and a reduction in risk factors for chronic diseases, discrepancies in explaining their positive effects have been found in terms of the bioavailability. In fact, polyphenols show a low bioavailability due to several factors: interaction with the food matrix, the metabolic processes mediated by the liver (phase I and II metabolism), intestine and microbiota. On the other hand, the biological activities of phenol compounds may be mediated by their metabolites, which are produced in vivo, and recent studies have confirmed that these molecules may have antioxidant and anti-phlogistic properties. This review discusses the studies performed in vivo, which consider the polyphenol bioavailability and their different food sources. Factors influencing the biological effects of the main classes of polyphenols are also considered.

Comparison of the pharmacokinetic profiles of 13 phenolic acids and 6 triterpenes in normal and leukopenia rats after oral administration of Sanguisorba officinalis L. extract by LC-MS/MS.

A selective, accurate, and efficient liquid chromatography-tandem mass spectrometry method was developed for the simultaneous determination of 13 phenolic acids. Additionally, for more comprehensively determining the chemical constituents in Sanguisorba officinalis L. extract, a previously developed method was employed for the simultaneous determination of six triterpenes. Thus, two methods were used to ensure the comprehensiveness and reliability of this study. Based on these methods, the pharmacokinetic profiles of the 13 phenolic acids and 6 triterpenes in normal and leukopenia rats after oral administration of S. officinalis L. extract were compared for the first time in the present study. Quantitative detection of the 13 phenolic acids and 6 triterpenes was performed using the multiple reaction monitoring mode with the electrospray ion source in negative and positive electrospray ionization, respectively. Chromatographic separation was performed on an Agilent Eclipse Plus C18 RRHD column (50 × 2.1 mm, 1.8 µm) using gradient elution with a mobile phase composed of methanol-0.1% aqueous formic acid. The pharmacokinetic results demonstrated that the pharmacokinetic characteristics of the 19 analytes in leukopenia rats differed significantly from those determined in normal rats, which could provide a helpful reference for the clinical application of S. officinalis L. in the prevention and treatment of leucopenia.

New progress in the pharmacology of protocatechuic acid: A compound ingested in daily foods and herbs frequently and heavily.

Protocatechuic acid is a natural phenolic acid, which widely exists in our daily diet and herbs. It is also one of the main metabolites of complex polyphenols, such as anthocyanins and proanthocyanins. In recent years, a large number of studies on the pharmacological activities of protocatechuic acid have emerged. Protocatechuic acid has a wide range of pharmacological activities including antioxidant, anti-inflammatory, neuroprotective, antibacterial, antiviral, anticancer, antiosteoporotic, analgesia, antiaging activties; protection from metabolic syndrome; and preservation of liver, kidneys, and reproductive functions. Pharmacokinetic studies showed that the absorption and elimination rate of protocatechuic acid are faster, with glucuronidation and sulfation being the major metabolic pathways. However, protocatechuic acid displays a dual-directional regulatory effect on some pharmacological activities. When the concentration is very high, it can inhibit cell proliferation and reduce survival rate. This review aims to comprehensively summarize the pharmacology, pharmacokinetics, and toxicity of protocatechuic acid with emphasis on its pharmacological activities discovered in recent 5 years, so as to provide more up-to-date and thorough information for the preclinical and clinical research of protocatechuic acid in the future. Moreover, it is hoped that the clinical application of protocatechuic acid can be broadened, giving full play to its characteristics of rich sources, low toxicity and wide pharmacological activites.

Comparative assessment of phenolic bioaccessibility from 100% grape juice and whole grapes.

Juicing of grapes includes contact with phenolic rich seeds and skins that otherwise rely on maceration for phenolic release. To understand if 100% grape juice can provide a matrix with highly bioaccessible phenolics relative to whole fruit, differences in phenolic content and bioaccessibility from commonly consumed table, Concord (CG) and Niagara (NG) grapes and their 100% juices were compared. Phenolic contents in whole grapes and 100% juices were assayed by LC-MS prior to in vitro digestion to determine phenolic bioaccessibility. Phenolic compounds were concentrated in CG and NG seeds as flavan-3-ols (222.2-285.5 mg per 100 g fw). CG skins were rich in anthocyanins (201.4 mg per 100 g fw) and flavonols (15.5 mg per 100 g fw). Product form had a significant impact on content (p < 0.01), relative bioaccessibility, and absolute bioaccessibility (p < 0.01). CG had a higher total phenolic content (21.9-50.7 mg per 100 g fw) compared to CGJ (5.8 mg per 100 g fw), though NG (4.9-10.8 mg per 100 g fw) was similar in phenolic content to NGJ (9.4-10.8 mg per 100 g fw). Absolute bioaccessibility of total phenolics from CGJ (5.2 mg per 100 g fw) was similar to CG (2.6-9.6 mg per 100 g fw), while NGJ (5.1-5.7 mg per 100 g fw) had higher bioaccessible phenolic content than NG (0.8-1.1 mg per 100 g fw). Differences in bioaccessible content were driven by high relative bioaccessibility of anthocyanins in CGJ (86-135%) compared to CG (14-39%) as well as for flavan-3-ols and phenolic acids from CGJ/NGJ (48-101; 39-85%) compared to CG/NG (0-3; 9-67%). Comparisons between juices and table grapes followed similar trends. A greater fraction of skin and seed phenolics was extracted through juicing and made bioaccessible, making 100% grape juice and whole fruit similar in phenolic delivery to consumers.

Antioxidant activity and bioaccessibility of phenolic compounds in white, red, blue, purple, yellow and orange edible flowers through a simulated intestinal barrier.

This study assessed the phenolics and their bioaccessibility through an in vitro digestion system coupled to a simulated intestinal barrier in eight edible flowers of distinct colors, namely mini rose, torenia, mini daisy, clitoria, cosmos, cravine, begonia and tagete. The antioxidant activity of the flowers before in vitro digestion, in their derived dialyzed and non-dialyzed fractions was evaluated using distinct approaches. All flowers presented in their composition phenolic acids, stilbenes, flavanol, anthocyanin, flavonol and flavanone, however distinct compounds and contents were found in each flower. The bioaccessibility varied among the phenolics and within the flower source (p < 0.05). Cosmos presented the highest (p < 0.05) content of phenolics and activity in ORAC assay before in vitro digestion and in dialyzed and non-dialyzed fraction; the observed activity was correlated (r = 0.9) to its major compounds, hesperidin and rutin, as well as to caftaric acid and procyanidin B2. Mini rose displayed the highest antioxidant activity in FRAP and DPPH assays before in vitro digestion; its dialyzed and non-dialyzed fraction showed the highest activity in FRAP, correlated to pelargonidin 3,5-diglucoside, catechin, epicatechin galate, epicagocatechin galate, procyanidin A2, quercitin 3-glucoside and trans-resveratrol (r = 0.9). In DPPH assay, mini rose showed the highest activity in the non-dialyzed fraction, while cravine showed the highest activity in the dialyzed fraction, which was mainly correlated to syringic acid (r = 1.0), pelargonidin 3,5-diglucoside and epicatechin (r = 0.9). Results show great variability in the phenolic composition and their bioaccessibility among the edible flowers studied. Our findings indicate cosmos and mini rose as sources of bioaccessible phenolics with great antioxidant activity.

Oxidative metabolism of typical phenolic compounds of Danshen by electrochemistry coupled to quadrupole time-of-flight tandem mass spectrometry.

An electrochemistry coupled to online quadrupole time-of-flight tandem mass spectrometry (EC/Q-TOF/MS) was applied to investigate the oxidative transformation and metabolic pathway of five phenolic acids in Danshen sample. Simulation of the phase I oxidative metabolism was carried out in an electrochemical reactor equipped with a glassy carbon working electrode. The phase II reactivity of the generated oxidative products towards biomolecules (such as glutathione) was investigated by ways of covalent adduct formation experiments. The results obtained by EC/MS were compared with well-known in vitro studies by conducting rat liver microsome incubations. Structures of the electrochemically produced metabolites were identified by accurate mass measurement and previously results in vivo metabolites. It was indicated that the electrochemical oxidation was in good accordance with similar products found in vivo experiments. In conclusion, this work confirmed that EC/Q-TOF/MS was a promising analytical tool in the prediction of metabolic transformations of functional foods.

Comparative absorption kinetics of seven active ingredients of Eucommia ulmoides extracts by intestinal in situ circulatory perfusion in normal and spontaneous hypertensive rats.

Eucommia ulmoides Oliv. (E. ulmoides) is a valuable and nourishing medicinal herb in China that has been used in the treatment of hypertension. Given the fact that most traditional Chinese medicine is mainly used to treat disease, investigating the pharmacokinetics of traditional Chinese medicines in the pathological state is more useful than that in the normal state. However, the differences in the absorption kinetics of active ingredients of E. ulmoides extract between pathological and physiological conditions have not been reported. Therefore, in this study, the rat intestinal in situ circulatory perfusion model was used to investigate the differences in absorption kinetics of seven active ingredients of E. ulmoides extract in normal and spontaneously hypertensive rats, namely, genipinic acid, protocatechuic acid, neochlorogenic acid, chlorogenic acid, cryptochlorogenic acid, (+)-pinoresinol di-O-ß-D-glucopyranoside and (+)-pinoresinol 4'-O-ß-D-glucopyranoside. Our results indicate that the pathological state of spontaneous hypertension may change the absorption of active components of E. ulmoides extracts, and these findings may provide a reference for improving the rational use of E. ulmoides in the clinic.

Comparative Pharmacokinetics of Gallic Acid, Protocatechuic Acid, and Quercitrin in Normal and Pyelonephritis Rats after Oral Administration of a Polygonum capitatum Extract.

Polygonum capitatum Buch.-Ham. ex D. Don is traditionally used by Hmong for the treatment of urinary tract infections and pyelonephritis. Information regarding the pharmacokinetic behavior of the extract in the condition of pyelonephritis is lacking. In the present study, we aimed to compare the pharmacokinetic properties of gallic acid (GA), protocatechuic acid (PCA), and quercitrin (QR)-the main bioactive constituents in the herb-in normal and pyelonephritis rats. The plasma samples were collected at various time points after administration of a single dose of Polygonum capitatum extract. The plasma level of GA, PCA, and QR at the designed time points was determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and drug concentration versus time plots were constructed to estimate the pharmacokinetic parameters. The AUC(0-t), AUC(0-∞), MRT(0-t), and CL of GA, PCA, and QR in pyelonephritis rats was significantly different from those of the normal rats. The results indicated that the three constituents have higher rate of uptake and slower rate of elimination in the rats with pyelonephritis, suggesting altered rate and extent of drug metabolism.

Total Phenolic and Flavonoid Content and Biological Activities of Extracts and Isolated Compounds of Cytisus villosus Pourr.

The aim of this study was to evaluate the total phenolic and flavonoid content, and the in vitro antioxidant, anti-inflammatory, antibacterial, antifungal, antimalarial, cytotoxicity, and antiprotozoal activities of the Algerian plant Cytisus villosus Pourr. (Syn. Cytisus triflorus L'Hérit.). Additionally, the radioligand displacement affinity on opioid and cannabinoid receptors was assessed for the extracts and isolated pure compounds. The hydro alcoholic extract of the aerial part of C. villosus was partitioned with chloroform (CHCl3), ethyl acetate (EtOAc), and n-butanol (n-BuOH). The phenolic content of the C. villosus extracts was evaluated using a modified Folin-Ciocalteau method. The total flavonoid content was measured spectrometrically using the aluminum chloride colorimetric assay. The known flavonoids genistein (1), chrysin (2), chrysin-7-O-ß-d-glucopyranoside (3), and 2″-O-α-l-rhamnosylorientin (4) were isolated. The antioxidant activities of the extracts and isolated compounds were evaluated using 2,2-diphenyl-1-picrylhydrazyl (DDPH) and cellular antioxidant activity (CAA) assays. The plant extracts showed moderate antioxidant activity. EtOAc and n-BuOH extracts showed moderate anti-inflammatory activity through the inhibition of induced nitric oxide synthase (iNOS) with IC50 values of 48 and 90 µg/mL, respectively. The isolated pure compounds 1 and 3 showed good inhibition of Inducible nitric oxide synthase (iNOS) with IC50 values of 9 and 20 µg/mL, respectively. Compounds 1 and 2 exhibited lower inhibition of Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) with IC50 values of 28 and 38 µg/mL, respectively. Furthermore, the extracts and isolated pure compounds have been shown to exhibit low affinity for cannabinoid and opioid receptors. Finally, n-BuOH extract was a potent inhibitor of Trypanosoma brucei with IC50 value of 7.99 µg/mL and IC90 value of 12.61 µg/mL. The extracts and isolated compounds showed no antimicrobial, antimalarial nor antileishmanial activities. No cytotoxic effect was observed on cancer cell lines. The results highlight this species as a promising source of anti-inflammatory and antitrypanosomal agents.

Chemical Composition and In Vitro Bioaccessibility of Antioxidant Phytochemicals from Selected Edible Nuts.

The ultimate health benefits of peanuts and tree nuts partially depend on the effective gastrointestinal delivery of their phytochemicals. The chemical composition and in vitro bioaccessibility of tocopherols, tocotrienols and phenolic compounds from peanuts and seven tree nuts were evaluated by analytical and chemometric methods. Total fat and dietary fiber (g 100 g-1) ranged from 34.2 (Emory oak acorn) to 72.5 (pink pine nut; PPN) and from 1.2 (PPN) to 22.5 (pistachio). Samples were rich in oleic and linoleic acids (56-87 g 100 g-1 oil). Tocopherols and tocotrienols (mg·kg-1) ranged from 48.1 (peanut) to 156.3 (almond) and 0 (almond, pecan) to 22.1 (PPN) and hydrophilic phenolics from 533 (PPN) to 12,896 (Emory oak acorn); flavonoids and condensed tannins (mg CE.100 g-1) ranged from 142 (white pine nut) to 1833 (Emory oak acorn) and 14 (PPN) to 460 (Emory oak acorn). Three principal components explained 90% of the variance associated with the diversity of antioxidant phytochemicals in samples. In vitro bioaccessibility of tocopherols, tocotrienols, hydrophilic phenolics, flavonoids, and condensed tannins ranged from 11-51%, 16-79%, 25-55%, 0-100%, and 0-94%, respectively. Multiple regression analyses revealed a potential influence of dietary fiber, fats and/or unsaturated fatty acids on phytochemical bioaccessibility, in a structure-specific manner.

Pro-Nifuroxazide Self-Assembly Leads to Triggerable Nanomedicine for Anti-cancer Therapy.

Transcription factor STAT3 has been shown to regulate genes that are involved in stem cell self-renewal and thus represents a novel therapeutic target of great biological significance. However, many small-molecule agents with potential effects through STAT3 modulation in cancer therapy lack aqueous solubility and high off-target toxicity, hence impeding efficient bioavailability and activity. This work, for the first time, reports a prodrug-based strategy for selective and safer delivery of STAT3 inhibitors designed toward metastatic and drug-resistant breast cancer. We have synthesized a novel lipase-labile SN-2 phospholipid prodrug from a clinically investigated STAT3 inhibitor, nifuroxazide (Pro-nifuroxazide), which can be regioselectively cleaved by the membrane-abundant enzymes in cancer cells. Pro-nifuroxazide self-assembled to sub 20 nm nanoparticles (NPs), and the cytotoxic ability was screened in ER(+)-MCF-7 and ER(-)-MD-MB231 cells at 48-72 h using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetra-zolium bromide proliferation assay. Results indicated that Pro-nifuroxazide NPs are multifold more effective toward inhibiting cancer cells in a time-dependent manner compared to parent nifuroxazide. A remarkable improvement in the local concentration of drugs to as high as ∼240 fold when assembled into NPs is presumably the reason for this functional improvement. We also introduced molecular dynamics simulations to generate Pro-nifuroxazide nano-assembly, as a model assembly from triggerable anti-cancer drugs, to provide molecular insights correlating physicochemical and anti-cancer properties. In silico properties of Pro-nifuroxazide including size, chemistry of NPs and membrane interactions with individual molecules could be validated by in vitro functional activities in cells of breast cancer origin. The in vivo anti-cancer efficiencies of Pro-nifuroxazide NPs in nude mice xenografts with MCF-7 revealed remarkable growth inhibition of as high as 400%. Histopathological analysis corroborated these findings to show significantly high nuclear fragmentation and retracted cytoplasm. Immunostaining on tumor section demonstrated a significantly lower level of pSTAT-3 by Pro-nifuroxazide NP treatment, establishing the inhibition of STAT-3 phosphorylation. Our strategy for the first time proposes a translatable prodrug agent self-assembled into NPs and demonstrates remarkable enhancement in IC50, induced apoptosis, and reduced cancer cell population through STAT-3 inhibition via reduced phosphorylation.

Particle size of milled chokeberry pomace did not influence in vitro cellular absorption and transport efficiencies of anthocyanins, phenolic acids and flavonols.

Industrial chokeberry pomace is very rich in polyphenols. The main focus here lies on the possible relationship between the particle size of chokeberry milled pomace and an enhanced absorption and transport of polyphenols by Caco-2 cells. Wet milling was used to produce materials with particle size distributions in the micrometre and in the sub-micrometre to nanometre ranges starting from chokeberry pomace. Milled materials with about 50% of the particles with a mean size (x50,3) of 223 ± 13 µm (coarse milling) and about 90% of the particles with x50,3 of 160 ± 40 nm (fine milling, sonication) were obtained. None of the milled materials exhibited cytotoxic effects within the tested concentration-ranges. The polyphenol absorption and the transport efficiencies from the fine and the coarse milled materials were similar. Thus, no effect of the particle size upon cellular uptake and transport could be established, but agglomeration of particle during incubation cannot be excluded as the cause. Furthermore, based on polyphenol stability we postulate that direct milling may be applied to valorise the processing by-product from commercial fruit juice production.

Mushroom ethanolic extracts as cosmeceuticals ingredients: Safety and ex vivo skin permeation studies.

Mushrooms are important sources of natural bioactive compounds that are increasingly used as cosmeceutical ingredients. In this context, ethanolic extracts were prepared from Ganoderma lucidum and Pleurotus ostreatus and tested by incorporation into base cosmetic creams. In vitro safety evaluation of the extracts and cosmetic formulations prepared therefore was carried out using the MTT and LDH assays in keratinocyte (HaCaT) and fibroblast (HFF-1) cell lines. Moreover, they were submitted to ex vivo skin permeation studies using a Franz diffusion apparatus with pig ear skin as permeation membrane. The results showed the absence of toxicity for keratinocytes and fibroblasts in a concentration dependent manner, which is indicative of the safety of these extracts for cosmeceutical ingredients purposes. Protocatechuic and syringic acids were the only compounds permeating from G. lucidum extract in the first 8 h of study, no penetration was observed for phenolic acids found in P. ostreatus extract and formulation. These results pointed out for the suitability of using mushroom extracts as skin care ingredients and may contribute for the valorisation of wastes generated by the mushroom processing industry, which can serve as raw-materials for the obtainment of the extracts.