Nutrikinetics and urinary excretion of phenolic compounds after a 16-week supplementation with a flavanone-rich ingredient.

Background: Polyphenols are a broad group of compounds with a complex metabolic fate. Flavanones and their metabolites provide cardiovascular protection and assistance in long-term body composition management. Objective: This study evaluates the nutrikinetics and the bioavailability of phenolic compounds after both acute and chronic supplementation with a flavanone-rich product, namely Sinetrol® Xpur, in healthy overweight and obese volunteers. Design: An open-label study including 20 volunteers was conducted for 16 weeks. Participants received Sinetrol® Xpur, either a low dose (900 mg per day) or a high dose (1800 mg per day), in capsules during breakfast and lunch. They were advised to follow an individualized isocaloric diet and avoid a list of polyphenol-rich foods 48 hours before and during the pharmacokinetic measurements. Results: Over 20 phase II and colonic metabolites were measured in the plasma. Two peaks were observed at 1 h and 7h-10 h after the first capsule ingestion. No significant differences in the AUC were observed in circulating metabolites between both doses. In urine excretion, 53 metabolites were monitored, including human phase II and colonic metabolites, at weeks 1 and 16. Cumulative urine excretion was higher after the high dose than after the low dose in both acute and chronic studies. Total urinary metabolites were significantly lower in week 16 compared to week 1. Conclusion: Although the urinary excreted metabolites reduced significantly over 16 weeks, the circulating metabolites did not decrease significantly. This study suggests that chronic intake might not offer the same bioavailability as in the acute study, and this effect does not seem to be dose-dependent. The clinical trial registry number is NCT03823196.

In Vitro Bioaccessibility Assessment of Phenolic Compounds from Encapsulated Grape Pomace Extract by Ionic Gelation.

Grape pomace is a by-product of winemaking characterized by a rich chemical composition from which phenolics stand out. Phenolics are health-promoting agents, and their beneficial effects depend on their bioaccessibility, which is influenced by gastrointestinal digestion. The effect of encapsulating phenol-rich grape pomace extract (PRE) with sodium alginate (SA), a mixture of SA with gelatin (SA-GEL), and SA with chitosan (SA-CHIT) on the bioaccessibility index (BI) of phenolics during simulated digestion in vitro was studied. A total of 27 individual phenolic compounds (IPCs) were quantified by UHPLC. The addition of a second coating to SA improved the encapsulation efficiency (EE), and the highest EE was obtained for SA-CHIT microbeads (56.25%). Encapsulation affected the physicochemical properties (size, shape and texture, morphology, crystallinity) of the produced microbeads, which influenced the delivery of phenolics to the intestine and their BI. Thus, SA-GEL microbeads had the largest size parameters, as confirmed by scanning electron microscopy (SEM), and the highest BI for total phenolic compounds and IPCs (gallic acid, 3,4-dihydroxybenzoic acid and o-coumaric acid, epicatechin, and gallocatechin gallate) ranged from 96.20 to 1011.3%. The results suggest that encapsulated PRE has great potential to be used as a functional ingredient in products for oral administration.

Inhibitory effects of phenolic glycosides from Trollius chinensis Bunge on α-glucosidase: inhibition kinetics and mechanisms.

Two undescribed phenolic glycosides, trochinenols B and C (1 and2), together with four known analogues (3-6), were isolated from the functional tea Trollius chinensis Bunge and their α-glucosidase inhibitory kinetics and mechanisms were investigated. It was found that 1 inhibited α-glucosidase in a noncompetitive manner with an IC50 value of 25.96 µM, while 3 showed a notable inhibitory effect against α-glucosidase in an uncompetitive manner with an IC50 value of 3.14 µM. Analysis of synchronous fluorescence and circular dichroism spectroscopy indicated that the binding of 1 to α-glucosidase led to the rearrangement and conformational alteration of the α-glucosidase enzyme. Furthermore, molecular docking indicated that 1 had a high affinity close to the active site pocket of α-glucosidase and indirectly inhibited the catalytic activity of the enzyme. However, 3 was bound to the entrance part of the active center of α-glucosidase and could hinder the release of the substrate as well as the catalytic reaction product, eventually suppressing the catalytic activity of α-glucosidase.

Role of Sulphur and Heavier Chalcogens on the Antioxidant Power and Bioactivity of Natural Phenolic Compounds.

The activity of natural phenols is primarily associated to their antioxidant potential, but is ultimately expressed in a variety of biological effects. Molecular scaffold manipulation of this large variety of compounds is a currently pursued approach to boost or modulate their properties. Insertion of S/Se/Te containing substituents on phenols may increase/decrease their H-donor/acceptor ability by electronic and stereo-electronic effects related to the site of substitution and geometrical constrains. Oxygen to sulphur/selenium isosteric replacement in resveratrol or ferulic acid leads to an increase in the radical scavenging activity with respect to the parent phenol. Several chalcogen-substituted phenols inspired by Vitamin E and flavonoids have been prepared, which in some cases prove to be chain-breaking antioxidants, far better than the natural counterparts. Conjugation of catechols with biological thiols (cysteine, glutathione, dihydrolipoic acid) is easily achieved by addition to the corresponding ortho-quinones. Noticeable examples of compounds with potentiated antioxidant activities are the human metabolite 5-S-cysteinyldopa, with high iron-induced lipid peroxidation inhibitory activity, due to strong iron (III) binding, 5-S-glutathionylpiceatannol a most effective inhibitor of nitrosation processes, and 5-S-lipoylhydroxytyrosol, and its polysulfides that proved valuable oxidative-stress protective agents in various cellular models. Different methodologies have been used for evaluation of the antioxidant power of these compounds against the parent compounds. These include kinetics of inhibition of lipid peroxidation alkylperoxyl radicals, common chemical assays of radical scavenging, inhibition of the OH• mediated hydroxylation/oxidation of model systems, ferric- or copper-reducing power, scavenging of nitrosating species. In addition, computational methods allowed researchers to determine the Bond Dissociation Enthalpy values of the OH groups of chalcogen modified phenolics and predict the best performing derivative. Finally, the activity of Se and Te containing compounds as mimic of glutathione peroxidase has been evaluated, together with other biological activities including anticancer action and (neuro)protective effects in various cellular models. These and other achievements are discussed and rationalized to guide future development in the field.

Olive Pomace Phenolic Compounds Stability and Safety Evaluation: From Raw Material to Future Ophthalmic Applications.

Nowadays, increasing interest in olive pomace (OP) valorization aims to improve olive's industry sustainability. Interestingly, several studies propose a high-value application for OP extracts containing its main phenolic compounds, hydroxytyrosol and oleuropein, as therapy for ocular surface diseases. In this work, the stability and accessibility of OP total phenolic and flavonoid content, main representative compounds, and antioxidant activity were assessed under different pretreatment conditions. Among them, lyophilization and supercritical CO2 extraction were found to increase significantly most responses measured in the produced extracts. Two selected extracts (CONV and OPT3) were obtained by different techniques (conventional and pressurized liquid extraction); Their aqueous solutions were characterized by HPLC-DAD-MS/MS. Additionally, their safety and stability were evaluated according to EMA requirements towards their approval as ophthalmic products: their genotoxic effect on ocular surface cells and their 6-months storage stability at 4 different temperature/moisture conditions (CPMP/ICH/2736/99), together with pure hydroxytyrosol and oleuropein solutions. The concentration of hydroxytyrosol and oleuropein in pure or extract solutions was tracked, and possible degradation products were putatively identified by HPLC-DAD-MS/MS. Hydroxytyrosol and oleuropein had different stability as standard or extract solutions, with oleuropein also showing different degradation profile. All compounds/extracts were safe for ophthalmic use at the concentrations tested.

Bioactivity, bioavailability, and gut microbiota transformations of dietary phenolic compounds: implications for COVID-19.

The outbreak of mysterious pneumonia at the end of 2019 is associated with widespread research interest worldwide. The coronavirus disease-19 (COVID-19) targets multiple organs through inflammatory, immune, and redox mechanisms, and no effective drug for its prophylaxis or treatment has been identified until now. The use of dietary bioactive compounds, such as phenolic compounds (PC), has emerged as a putative nutritional or therapeutic adjunct approach for COVID-19. In the present study, scientific data on the mechanisms underlying the bioactivity of PC and their usefulness in COVID-19 mitigation are reviewed. In addition, antioxidant, antiviral, anti-inflammatory, and immunomodulatory effects of dietary PC are studied. Moreover, the implications of digestion on the putative benefits of dietary PC against COVID-19 are presented by addressing the bioavailability and biotransformation of PC by the gut microbiota. Lastly, safety issues and possible drug interactions of PC and their implications in COVID-19 therapeutics are discussed.

Metabolic Fate and Cardiometabolic Effects of Phenolic Compounds from Red-Fleshed Apple in Hypercholesterolemic Rats: A Comparative Study with Common White-Fleshed Apple. The AppleCOR Study.

The present study aims to investigate the metabolic fate and the cardiometabolic effects of phenolic compounds provided by a red-fleshed apple variety biofortified in anthocyanins (ACN). Wistar rats are fed with high-fat diet (HFD) to induce hypercholesterolemia and supplemented with red-fleshed apple (HFD+R), white-fleshed apple (HFD+W), or an ACN-rich infusion from aronia fruit (HFD+A) providing matched content and profile of ACN. Plasma biochemical parameters, histological analysis, and phenol biological metabolites are determined. Plasma, urine, and feces show a significant increase of ACN metabolites after HFD+R and HFD+A, while flavan-3-ols are significantly increased after HFD+W and dihydrochalcones derivatives increased after both apples supplementation. A cardioprotective effect is observed after both apples and aronia infusion supplementation in the reduction of aortic thickness. The kidney function is improved after all supplementations and a decrease in insulin plasma concentration after both apples supplementation (HFD+R and HFD+W) is also observed. The findings support that ACN without apple matrix can induce cardioprotective effects. ACN or flavan-3-ols, together with dihydrochalcones, compose a phenolic phytocomplex in red- and white-fleshed apples, respectively, which can act synergistically in the attenuation of cardiovascular outcomes in hypercholesterolemic rats.

Protective Effects of Morus nigra and Its Phytochemicals against Hepatotoxicity: A Review of Preclinical Studies.

BACKGROUND: Our liver has a variety of vital functions including removing poisons, storing energy, immunological roles, and secretory and excretory functions. It may face some kinds of diseases caused by viruses, hepatotoxic chemicals, drugs, alcohol, and inherited disorders. Oxidative stress and inflammation are in the core of mechanisms of liver damages induced by viruses or chemical agents. SUMMARY: Morus nigra (M. nigra), generally known as black mulberry, exhibited wide-spectrum pharmacological effects including antidiabetic, antinociceptive, anticancer, and hepatoprotective activities. Different parts of this plant particularly the fruit and leaf have shown beneficial effects on hepatocytes in cell culture and animal models of liver damages induced by chemicals (e.g., CCl4), drugs (e.g., paracetamol), diet (e.g., high fat), diabetes, etc. The beneficial effects of M. nigra on the liver are attributed to the presence of considerable amounts of phenolic compounds such as anthocyanins, flavonols, and phenolic acids. The present review is aimed to focus on the hepatoprotective activities of M. nigra and its phytochemicals and the mechanisms responsible for these activities. Key Messages: The evidence reviewed in this study can help design clinical trials on M. nigra in patients with liver disorders and develop a hepatoprotective herbal medicine.

Pharmacokinetics and tissue distribution study of 15 ingredients of Polygonum chinense Linn extract in rats by UHPLC-MS/MS.

A rapid and sensitive ultrahigh-performance liquid chromatography-tandem mass spectrometry method was developed and validated for simultaneous determination of 15 bioactive ingredients in rat plasma and tissues after oral administration of Polygonum chinense Linn extract (PCE). After addition of internal standards (ISs; rutin and danshensu), plasma and tissue samples were pre-treated by protein precipitation with acetonitrile-ethanol. The chromatographic separation was performed on an Agilent ZORBAX RRHD Eclipse Plus C18 column with gradient elution using a mobile phase composed of methanol and water (containing 0.2% acetic acid) at a flow rate of 0.3 mL min-1 . Mass spectrometric detection was carried out using a mass spectrometer in both positive and negative ion electrospray ionization modes by multiple reaction monitoring. The method provided excellent linearity, and the lower limit of quantification range 0.5-30 ng mL-1 for all analytes. The intra- and inter-day precision were less than 9.12% and the accuracy ranged from -4.02% to 6.32%, respectively. The mean extraction recovery and matrix effect of analytes and ISs ranged from 83.65% to 109.20%. The method was successfully applied to the pharmacokinetics and tissue distribution study of 15 ingredients of PCE in rats.

Dietary Phenolics against Breast Cancer. A Critical Evidence-Based Review and Future Perspectives.

Breast cancer (BC) is the most common malignancy and the leading cause of cancer-related death in adult women worldwide. Over 85% of BC cases are non-hereditary, caused by modifiable extrinsic factors related to lifestyle, including dietary habits, which play a crucial role in cancer prevention. Although many epidemiological and observational studies have inversely correlated the fruit and vegetable consumption with the BC incidence, the involvement of their phenolic content in this correlation remains contradictory. During decades, wrong approaches that did not consider the bioavailability, metabolism, and breast tissue distribution of dietary phenolics persist behind the large currently existing gap between preclinical and clinical research. In the present review, we provide comprehensive preclinical and clinical evidence according to physiologically relevant in vitro and in vivo studies. Some dietary phenolics such as resveratrol (RSV), quercetin, isoflavones, epigallocatechin gallate (EGCG), lignans, and curcumin are gaining attention for their chemopreventive properties in preclinical research. However, the clinical evidence of dietary phenolics as BC chemopreventive compounds is still inconclusive. Therefore, the only way to validate promising preclinical results is to conduct clinical trials in BC patients. In this regard, future perspectives on dietary phenolics and BC research are also critically discussed.

Salidroside as a potential neuroprotective agent for ischemic stroke: a review of sources, pharmacokinetics, mechanism and safety.

Salidroside (Sal) is a bioactive extract principally from traditional herbal medicine such as Rhodiola rosea L., which has been commonly used for hundreds of years in Asia countries. The excellent neuroprotective capacity of Sal has been illuminated in recent studies. This work focused on the source, pharmacokinetics, safety and anti-ischemic stroke (IS) effect of Sal, especially emphasizing its mechanism of action and BBB permeability. Extensive databases, including Pubmed, Web of science (WOS), Google Scholar and China National Knowledge Infrastructure (CNKI), were applied to obtain relevant online literatures. Sal exerts powerful therapeutic effects on IS in experimental models either in vitro or in vivo due to its neuroprotection, with significantly diminishing infarct size, preventing cerebral edema and improving neurological function. Also, the findings suggest the underlying mechanisms involve anti-oxidation, anti-inflammation and anti-apoptosis by regulating multiple signaling pathways and key molecules, such as NF-κB, TNF-α and PI3K/Akt pathway. In pharmacokinetics, although showing a rapid absorption and elimination, bioavailability of Sal is elevated under some non-physiological conditions. The component and its metabolite (tyrosol) are capable of distributing to brain tissue and the later keeps a higher level of concentration. Moreover, Sal scarcely has obvious toxicity or side effects in a variety of animal experiments and clinical trials, but combination of drugs and perinatal use of medicine should be taken more attentions. Finally, as an active ingredient, not only is Sal isolated from diverse plants with limited yield, but also large batches of the products can be harvested by biological and chemical synthesis. With higher efficacy and better safety profiles, Sal could sever as a promising neuroprotectant for preventing and treating IS. Nevertheless, further investigations are still required to explore the pharmacodynamic and pharmacokinetic properties of Sal in the treatment of IS.

Formulation of a Phenol-Rich Extract from Unripe Olives (Olea europaea L.) in Microemulsion to Improve Its Solubility and Intestinal Permeability.

The beneficial properties of phenolic compounds from Olea europaea L. are well-known. An olive extract (OE) was prepared from unripe olives (Moraiolo cultivar). The study aimed to formulate OE into a microemulsion (ME) in oral dosage form. OE was extracted from olives with EtOH:H2O (80:20) and characterized by HPLC-DAD. ME composition was stated by a solubility and pseudo-ternary diagram. The ME was chemically and physically characterized, and its stability at 4 °C was analyzed for three months. The ability of the formulation to ameliorate the solubility and the intestinal permeability of OE was evaluated by a Parallel Artificial Membrane Permeability Assay (PAMPA) assay and Caco-2 cells. The total phenolic content of the extract was 39% w/w. The main constituent was oleuropein (31.0%), together with ligstroside (3.1%) and verbascoside (2.4%). The ME was prepared using Capryol 90 as the oily phase, and Cremophor EL and Transcutol (2:1) as surfactant and co-surfactant, respectively. ME droplet size was 14.03 ± 1.36 nm, PdI 0.20 ± 0.08, ζ-potential -1.16 ± 0.48. Stability of ME was confirmed for at least three months. The formulation was loaded with 35 mg/mL of OE, increasing the solubility of the extract by about four times. The enhanced permeability of OE was evaluated by PAMPA, as demonstrated by the Pe value (1.44 ± 0.83 × 10-6 cm/s for OE hydroalcoholic solution, 3.74 ± 0.34 × 10-6 cm/s for OE-ME). Caco-2 cell transport studies confirmed the same results: Papp was 16.14 ± 0.05 × 10-6 cm/s for OE solution and 26.99 ± 0.45 × 10-6 cm/s for OE-ME. ME proved to be a suitable formulation for oral delivery.

Physicochemical stability and in vitro bioaccessibility of phenolic compounds and anthocyanins from Thai rice bran extracts.

The processing and digestive stability of ethanolic extracts from four Thai rice bran varieties, namely Khao Dawk Mali 105, Hom Nil, Kiaw Ngu, and Leum Pua, were assessed by applying different thermal and pH conditions, as well as in vitro gastrointestinal digestion models. High-performance liquid chromatography, Folin-Ciocalteu analysis, as well as 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity and ferric reducing antioxidant power (FRAP) assays were used to determine the chemical composition, total phenolic content (TPC), and antioxidant activity. Thermal treatment at 100 °C for 15 min induced the degradation of phenolic components and TPC, whereas the antioxidant activities measured by DPPH and FRAP assays remained stable after the heat treatment. Higher phenolic content and antioxidant activity values were observed in the extracts incubated at acidic pH levels of 3 and 5. After simulated digestion, all extracts exhibited the decrease of phenolic compounds and anthocyanin contents, as well as antioxidant activities.

Effects of steam explosion pretreatment on the composition and biological activities of tartary buckwheat bran phenolics.

Steam explosion (SE) is an efficient technology to disrupt materials for improving their quality. In this study, SE was applied to release phenolics and improve the roughening of tartary buckwheat bran. The results showed that SE promoted the dissolution of phenolics, particularly, the content of the bound fraction was nearly increased by two times (0.36 vs. 0.99 mg GAE per g DW). The analysis of the phenolic composition showed that SE improved the liberation of bound pyrogallic acid, protocatechuic acid and caffeic acid. The biological activity tests indicated that SE effectively enhanced the oxygen radical absorbance capacity (ORAC) in vitro of the extract of bound phenolics by 270%. It also improved the cellular antioxidant activity (CAA) in vitro of the extract of free phenolics by 215%. Furthermore, SE showed potential in improving the antiproliferative activity of the total phenolic extract against Caco-2 cells as well as the bound phenolic extract against HepG2 cells in vitro.

Antibacterial and cytotoxic activities of phenolic constituents from the stem extracts of Spatholobus parviflorus.

A new 2-arylbenzofuran, spathobenzofuran (1), together with ten known compounds including a 2-arylbenzofuran, three pterocarpans and six isoflavones were isolated from the acetone crude extract of the stems of Spatholobus parviflorus. All compounds were characterised by spectroscopic methods. Compound 4 was active (MIC 8 µg/mL) against Gram-negative Pseudomonas aeruginosa TISTR 781 while compound 2 had modest activity against Gram-positive Staphylococcus aureus TISTR 1466 with a MIC value of 16 µg/mL. All isolated compounds showed no cytotoxicity against Vero and KB cells.

Analysis of five active ingredients of Er-Zhi-Wan, a traditional Chinese medicine water-honeyed pill, using the biopharmaceutics classification system.

Er-Zhi-Wan (EZW) is a traditional Chinese medicine with many clinical applications and used as a health product in East Asia. Five active ingredients (salidroside, specnuezhenide, nuezhenoside, luteolin, and oleanolic acid) were screened out from EZW to develop an in vitro rapid evaluation method for the classification of in vivo drug absorption behavior by biopharmaceutics classification system (BCS). Ultra-performance liquid chromatography was used for quantitative analysis. Solubility and permeability were assayed by equilibrium solubility and multiple models: everted rat intestinal sac model, cultured Caco-2 cells, octanol-water partition coefficient (LogP) method. The BCS properties of drugs were predicted using software applications, and the correlations of measured and predicted values of factors affecting oral drug absorption were calculated. The results were verified by measuring the absolute bioavailability of the active ingredients. Salidroside, specnuezhenide, and nuezhenoside were classified as BCS class III drugs, and luteolin was classified as a BCS class III/I drug because of the difference in LogP and intestinal permeability. Oleanolic acid was classified as a BCS class II/IV drug in acidic media and BCS class I/III drug in other media. Overall, EZW may be classified as a BCS class III drug, and permeability was identified as the primary factor limiting absorption. The results provide a novel method for the evaluation of the in vivo absorption of oral traditional Chinese medicines.

Effects of probiotics on the content and bioaccessibility of phenolic compounds in red pitaya pulp.

This study assessed the effects of the incorporation of Lactobacillus acidophilus LA-05 or Bifidobacterium animalis ssp. lactis BB-12 in the content and bioaccessibility of phenolics in red pitaya pulp. The oxygen radical absorbance capacity (ORAC) of the dialyzed (bioaccessible) fraction of red pitaya pulp fermented by these probiotics was also assessed. After 48 h of cultivation in red pitaya pulp, the pH and sugar contents decreased, while organic acids and viable counts of the tested probiotics increased (p < 0.05). After exposure to simulated gastrointestinal conditions the viable counts of L. acidophilus LA-05 and B. lactis BB-12 in fermented red pitaya pulp were close to 8 and 7 log CFU/mL, respectively. Fermentation with probiotics decreased (p < 0.05) the contents of phenolic acids and flavonoids in red pitaya pulp. Both, L. acidophilus LA-05 and B. lactis BB-12 increased the presence of phenolics in the non dialyzed fraction of the red pitaya pulp. The bioaccessibility of catechin, epigallocatechin gallate, and procyanidin B2 increased (p < 0.05) in red pitaya pulp fermented by L. acidophilus LA-05 or B. lactis BB-12. The bioaccessible fraction of red pitaya pulp fermented by L. acidophilus LA-05 or B. lactis BB-12 showed higher antioxidant activity than that of the non-fermented red pitaya pulp. These findings indicate the fermentation of red pitaya by probiotics as an alternative to increase the bioaccessibility of specific phenolics, as well as the antioxidant activity in this fruit.

Improvement of phenolic compound bioaccessibility from yerba mate (Ilex paraguariensis) extracts after biosorption on Saccharomyces cerevisiae.

Great efforts have been made to increase the bioaccessibility of bioactive compounds from plant sources. This can be achieved by the innovative and effective method of biosorption of these compounds in Saccharomyces cerevisiae obtained from the industrial fermentative process (waste yeast). In this context, this research evaluated if chemical modifications of depleted yeast can improve the capacity to biosorb the phenolic compounds and if through in vitro digestion tests, this approach can increase bioaccessibility of the secondary metabolites from yerba mate. The results showed that the chemical modification of the yeast promoted an increase in the biosorption efficiency of the bioactive compounds. Mass spectrometry peaks for the phenolic compounds reduced after biosorption as observed for the caffeic and dicaffeoylquinic acids and for kaempferol and rutin. In addition, a 10% reduction of caffeine was verified after biosorption, quantified by mass spectrometry chromatography. This showing that the compounds were retained in the cells, which was also observed by an increase of cell turgidity with scanning electron microscopy (SEM). Mid-infrared spectroscopy showed that the major bands related to the components of the compounds increased proportionally after biosorption. Furthermore, an increase of bioaccessibility of the yerba mate bioactive compounds adsorbed in S. cerevisiae was verified when compared with the crude extract.

Simultaneous Quantification of Four Phenylethanoid Glycosides in Rat Plasma by UPLC-MS/MS and Its Application to a Pharmacokinetic Study of Acanthus Ilicifolius Herb.

Acanthus ilicifolius herb (AIH), the dry plant of Acanthus ilicifolius L., has long been used as a folk medicine for treating acute and chronic hepatitis. Phenylethanoid glycosides (PhGs) are one family of the main components in AIH with hepatoprotective, antioxidant, and anti-inflammatory activities. In this study, the pharmacokinetics of AIH was investigated preliminarily by ultra-performance liquid chromatography coupled with triple quadrupole mass spectrometry (UPLC-MS/MS). A simultaneously quantitative determination method for four PhGs (acteoside, isoacteoside, martynoside, and crenatoside) in rat plasma was first established by UPLC-MS/MS. These four PhGs were separated with an ACQUITY UPLC BEH C18 column (2.1 × 50 mm, 1.7 µm) by gradient elution (mobile phase: MeCN and 0.1% formic acid in water, 0.4 mL/min). The mass spectrometry detection was performed using negative electrospray ionization (ESI-) in multiple reaction monitoring (MRM) mode. By the established method, the preliminary pharmacokinetics of AIH was elucidated using the kinetic parameters of the four PhGs in rat plasma after intragastric administration of AIH ethanol extract. All four PhGs showed double peaks on concentration-time curves, approximately at 0.5 h and 6 h, respectively. Their elimination half-lives (t1/2) were different, ranging from 3.42 h to 8.99 h, although they shared similar molecular structures. This work may provide a basis for the elucidation of the pharmacokinetic characteristics of bioactive components from AIH.

Sorafenib-loaded hydroxyethyl starch-TG100-115 micelles for the treatment of liver cancer based on synergistic treatment.

Tumor microenvironment is closely related to the occurrence and development of liver cancer. Tumor-associated macrophages (TAMs) are an important part of tumor microenvironment promoting tumor deterioration and metastasis by inhibiting immune cells. Previous studies showed that PI3Kγ inhibitor could reverse the phenotype of TAMs, relieve immunosuppression and sensitize chemotherapy drugs, suggesting that the combination of PI3Kγ inhibitor and chemotherapeutics is likely to bring new breakthroughs in the treatment of liver cancer. Based on it, this paper builds HES-TG100-115-CDM-PEG micelles with tumor microenvironment responsiveness that simultaneously loaded sorafenib and TG100-115 to synergistically treat liver cancer. Pharmacokinetic study showed that the prepared micelles had longer half-life than that of the free drug solutions, which was favorable for high propensity of extravasation through tumor vascular fenestrations. Under low pH and high α-amylasereductive conditions, micelles could depolymerize quickly due to the sensitivity of bonds and enhance significantly cytotoxic activity against Hep-3B liver cancer cell. Additionally, micelles demonstrated higher levels of antitumor efficiency and better tolerance against nude mouse with Hep-3B cell than the free drug solutions. These findings reveal that HES-TG100-115-CDM-PEG micelles are a promising drug delivery system in clinical comprehensive therapy of liver cancer.