Triple Recycling Processes Impact Systemic and Local Bioavailability of Orally Administered Flavonoids

Triple recycling (i.e., enterohepatic, enteric and local recycling) plays a central role in governing the disposition of phenolics such as flavonoids, resulting in low systemic bioavailability but higher gut bioavailability and longer than expected apparent half-life. The present study aims to investigate the coexistence of these recycling schemes using model bioactive flavonoid tilianin and a four-site perfused rat intestinal model in the presence or absence of a lactase phlorizin hydrolase (LPH) inhibitor gluconolactone and/or a glucuronidase inhibitor saccharolactone. The result showed that tilianin could be metabolized into tilianin glucuronide, acacetin, and acacetin glucuronide, which are excreted into the bile and luminal perfusate (highest in the duodenum and lowest in the colon). Gluconolactone (20 mM) significantly reduced the absorption of tilianin and the enteric and biliary excretion of acacetin glucuronide. Saccharolactone (0.1 mM) alone or in combination of gluconolactone also remarkably reduced the biliary and intestinal excretion of acacetin glucuronide. Acacetin glucuronides from bile or perfusate were rapidly hydrolyzed by bacterial β-glucuronidases to acacetin, enabling enterohepatic and enteric recycling. Moreover, saccharolactone-sensitive tilianin disposition and glucuronide deconjugation, which was more active in the small intestine than the colon, points to the small intestinal origin of the deconjugation enzyme and supports the presence of local recycling scheme. In conclusion, our studies have demonstrated triple recycling of a bioactive phenolic (i.e., a model flavonoid), and this recycling may have an impact on the site and duration of polyphenols pharmacokinetics in vivo.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-015-9732-x) contains supplementary material, which is available to authorized users.KEY WORDS: enteric recycling, enterohepatic recycling, flavonoid, local recycling, phase II metabolism     

采用PRECEDE模式探讨影响初产妇 母乳喂养率的因素

目的 采用PRECEDE (predisposing, reinforcing, enabling constructs in educational diagnosis and evaluation)模式分析影响初产妇母乳喂养率的相关因素。方法 选取产科2013年1月-2015年12月收治的260例住院分娩初产妇为研究对象,根据PRECEDE模式设计量表对所有产妇进行评估。记录产妇的PRECEDE评分与产后6个月内纯母乳喂养率,对影响母乳喂养的因素进行单因素分析,并进行logistic回归分析。结果 260例初产妇出院时及产后1~6个月母乳喂养率分别为80.76%、77.31%、72.69%、63.84%、56.15%、49.62%、36.92%。倾向因素中母乳喂养知识、母乳喂养态度、理想喂养方式,强化因素中社会环境认同、家庭成员支持是影响纯母乳喂养的因素。结论 医护人员应加强初产妇产后喂养知识和技能的培训,鼓励产妇进行纯母乳喂养,以提高初产妇母乳喂养率。     

Renewable juglone nanowires with size-dependent charge storage properties

Inspired by the biological metabolic process, some biomolecules with reversible redox functional groups have been used as promising electrode materials for rechargeable batteries, supercapacitors and other charge-storage devices. Although these biomolecule-based electrode materials possess remarkable beneficial properties, their controllable synthesis and morphology-related properties have been rarely studied. Herein, one dimensional nanostructures based on juglone biomolecules have been successfully fabricated by an antisolvent crystallization and self-assembly method. Moreover, the size effect on their electrochemical charge-storage properties has been investigated. It reveals that the diameters of the one dimensional nanostructure determine their electron/ion transport properties, and the juglone nanowires achieve a higher specific capacitance and rate capability. This work will promote the development of environmentally friendly and high-efficiency energy storage electrode materials.

Renewable juglone nanowires have been successfully fabricated, and their size effect on electrochemical charge-storage properties has been investigated.

Currently, the development of high-performance electrochemical energy-storage materials and devices is attracting intensive interest. Conventional electrode materials involving transition metal compounds,^1–4 elementary substances,^5–8 and conductive polymers,^9–12 with superior charge storage properties have been widely investigated. However, the poor biocompatibility, rising prices and depletion issues limit their sustainable applications due to their intrinsic material properties.¹³ Thus, exploring naturally abundant and renewable charge-storage materials with promising electrochemical performance is of great significance.In the biological system, its metabolic process mainly relies on ions transport and energy exchanges of redox-active biomolecules with special functional groups such as carbonyl groups, carboxyl groups, and pteridine centres.¹⁴ Due to their abundance, sustainability, environmental benignity, these renewable and nature-derivable biomolecules with well-defined charge-storage behaviors are ideal alternatives to conventional electrode materials for the next-generation green energy-storage devices.^15–17 For instance, biomolecules such as lignin,¹⁸ melanin,¹⁹ riboflavin,²⁰ juglone²¹ and humic acid²² have been demonstrated as promising electrode materials for the rechargeable batteries, supercapacitors and other charge-storage devices. Although these biomolecule-based electrode materials possess remarkable beneficial properties, they are still confronted with several serious problems of poor conductivity and high electrochemical reaction impedance.²³ For some conventional inorganic and organic active electrode materials, decreasing their size has been demonstrated to be effective strategies to enhance the electrochemical reaction kinetics by exposing more active sites to electrolytes and conductive agent.^8,24,25 These results have strongly motivated us to develop biomolecule-based nanostructures, and investigated their size-correlative charge storage behavior.^26,27Herein, one dimensional (1D) nanostructures based on juglone, a renewable redox-active biomolecule which can be derived from matured fruits of black walnut and the green peel of juglandaceae, have been successfully fabricated by an antisolvent crystallization and self-assembly method.^28–30 The size effect on the electrochemical charge-storage properties of these biomolecule-based 1D nanostructures have been investigated. It reveals that the electronic/ionic transport properties and charge-storage performance can be modulated by the size of self-assembled 1D nanostructures, and the samples with smaller diameter realize the higher specific capacitance and rate capability. Our work will provide insights for the development of high-performance biomolecule-based green energy-storage materials and devices.Juglone, also called 5-hydroxy-1,4-naphthalenedione, is a nature-derivable biomolecule, and displays a well-defined redox behavior in acetonitrile due to its quinone groups (Fig. 1a and b).³¹ As organic molecule inherently, it is soluble in organic solvent and difficult to dissolve in water, so its nano-architectures could be condonably fabricated by an antisolvent crystallization strategy (Fig. 1c) and would carry out stably for charge storage in an aqueous electrolyte.^29,30 Firstly, the juglone-biomolecule-based 1D nanostructures with different size were synthesized. The juglone micropillars with a mean diameter around 12 μm were prepared by directly recrystallizing a water/acetonitrile mixed solution of juglone at room temperature (Fig. 2a and d). Compared to commercially available raw juglone materials (Fig. S1^†), the juglone micropillars could increase its charge storage performance, but its relative large size would still confine its contact with electrolyte, and thus remarkably reduce the reaction kinetics.³² To further improve the potential reaction kinetics, the juglone microwires with an average diameter about 1 μm (Fig. 2b and e) and juglone nanowires with a mean diameter about 550 nm (Fig. 2c and f) were fabricated at room temperature using the reprecipitation method.³³ In the specific synthesis process, a high-concentration juglone acetonitrile solution is injected into water, which is a poor solvent for juglone molecules. Under stirring, juglone started to crystallize within a few seconds owing to its poor solubility in the water/acetonitrile mixture solvent and self-assembled into 1D nanostructures, and this procedure could be resulted from the π–π interaction.²⁹ It can be found that the diameter of 1D juglone materials is adjustable by tuning the concentration of juglone in acetonitrile, and the higher concentration of juglone acetonitrile solution yields the smaller size of 1D juglone materials. The insert panels show the percentage of juglone micropillar, microwire, nanowire with different diameter coverage (Fig. 2d–f).Open in a separate windowFig. 1(a) Chemical structural formula of juglone biomolecules which can be derived from the bark of black walnuts. (b) Juglone redox activity verified in a mixed solution of acetonitrile/deionized water by a three-electrode system using Pt foils as both the counter and working electrodes, Ag/AgCl as the reference electrode, and 2.3 M H₂SO₄ as the electrolyte. (c) Schematically illustration of the fabrication of the juglone nanowire/microwire.Open in a separate windowFig. 2SEM images of juglone 1D nanostructures at different magnification. (a and d) Juglone micropillar, (b and e) juglone microwire, (c and f) juglone nanowire. The insert images in panels (d–f) are corresponding mathematical statistic results of juglone samples with different diameter.Generally, the covalent bond, hydrogen bond, van der Waals forces, electrostatic forces, surface tension forces/dewetting, and π–π stacking interactions are considered as the effective factors in the self-assembly procedure of organic compounds.^34–36 The juglone biomolecule has a α-naphthol backbone with two carbonyl groups, which may induce the molecules self-assembly by the π–π interactions.^29,37–39 Fourier Transform Infrared Spectroscopy (FTIR) of such samples was utilized to examine the ingredient of these samples. As shown in Fig. S2,^† all the samples show similar characteristic peaks, the peak at 1640 cm⁻¹ is attributed to the stretching vibration of carbonyl groups, which is the main reversible redox center presented in juglone molecules. Meanwhile, Raman spectra also corroborated the results (Fig. S4^†). The crystal structures of these samples are further characterized by X-ray diffraction (XRD) as shown in Fig. S3.^† No impurity peak is observed in these patterns, demonstrating that these samples have the same crystal structure. And the peak intensity of juglone nanowire is stronger than juglone microwire and micropillar, suggesting that juglone nanowires have high crystallinity and relatively uniform crystal size.³⁰To investigate the redox behavior of 1D juglone micro/nanostructures, the cyclic voltammetry (CV) measurements were firstly performed (Fig. 3a), and the result reveals that these samples show a superior reversible redox performance, implying a potential application as energy storage materials. Meanwhile, compared with the CV curves of raw juglone, juglone micropillar and juglone microwire, the juglone nanowire exhibits the strongest redox peak, suggesting that the juglone nanowire-based electrode has a better charge storage behavior. To further evaluate the electrochemical performance of these samples, galvanostatic charge–discharge (GCD) measurements were carried out (Fig. 3b). First, juglone nanowire shows a higher specific capacity than that of microwire and micropillar. Besides, the plot of juglone 1D-based electrodes exhibit symmetric triangular shape with one pair of charge–discharge voltage plateau, and the voltage plateau of juglone micropillar, microwire and nanowire appears at 0.28 V, 0.26 V, 0.22 V, which is roughly consistent with the results of CV curves. Furthermore, it further reveals that the 1D nanostructure with smaller size exhibits higher specific capacity during the scan rates increasing from 10 to 200 mV s⁻¹ (Fig. 3c). In detail, at a low scan rate of 10 mV s⁻¹, the specific capacity delivered by juglone nanowire, juglone microwire, juglone micropillar are 389 F g⁻¹, 375 F g⁻¹, 116 F g⁻¹, respectively, and these samples possess the specific capacities of 232 F g⁻¹, 205 F g⁻¹, 80 F g⁻¹, when the scan rate are enhanced to 200 mV s⁻¹. The general perception is that nanomaterials with higher specific surface areas usually possess better electrochemical performance.⁴⁰ Obviously, the higher specific capacitance and superior rate capability are achieved by juglone nanowire electrode.Open in a separate windowFig. 3Electrochemical performance of the juglone samples with different diameter. (a) CV curves of juglone micropillar, microwire, nanowire electrodes in the potential range of −0.1 to 0.7 V (vs. Ag/AgCl) with a scan of 50 mV s⁻¹, (b) galvanostatic charge–discharge curves of juglone electrodes with different diameter at 2 A g⁻¹. (c) Statistical study of the rate performance conducted at each scan rate based on the cyclic voltammetry capacity of five electrodes as one batch. (d) Impedance phase angle as a function of frequency for juglone micropillar, microwire, nanowire electrodes. Inset is the Nyquist plot of them. (e) Correlation between the diameter and the specific capacity of the juglone samples at various scan rates.Then, the reaction kinetics of juglone with different sizes were investigated by electrochemical impedance spectroscopy (EIS) (Fig. 3d and S5^†). The crooked curve at high frequency denotes the interface resistance, involving contact and charge transfer resistances, while the low-frequency line represents ion diffusion resistance. The interface resistances of juglone nanowire, microwire, micropillar, raw material electrodes are 3.45 Ω, 3.80 Ω, 3.95 Ω, 4.02 Ω. The plot of the phase angle against the frequency reveals the characteristic frequency f₀ at the phase angle of −45° is 7.46 Hz for juglone nanowire-based electrode, and it is relatively higher than that for juglone microwire (7.36 Hz), micropillar (7.25 Hz) and raw material (6.48 Hz). Accordingly, the time constant t₀ (t₀ = 1/f₀) that represents the minimum time to discharge ≥50% of all the energy from the electrode was 0.134 s for juglone nanowire, whereas 0.136 s, 0.138 s, 0.154 s were required for juglone microwire, micropillar and raw material. The low charge transfer resistance, and short time constant validated the excellent charge and discharge capability of the juglone nanowire-based electrode.⁴¹In addition, for solid-state diffusion of H⁺ in electrode materials, the mean diffusion time is proportional to the square of the diffusion path length according to the following equation:t ≈ L²/D_H⁺1where L is the diffusion length and D_H⁺ the diffusion constant.^42,43 It has been found that the diffusion pathway will be shortening by nanostructuring of electrode materials when the diffusion constant D is same,⁴⁴ indicating that the smaller size nanostructures of juglone facilitate rapid ion/electron transport. Thus, 1D juglone nanowires possess higher specific capacitance and show slower capacity decay during the increased scan rates (Fig. 3e).Furthermore, the CV and GCD for juglone nanowire-based electrodes were tested under various scan rates and current densities. The CV profiles show that the redox activity can be maintained very well when increasing the scan rate from 10 to 100 mV s⁻¹ (Fig. 4a). Moreover, the GCD curves collected at different current densities exhibit symmetric triangular shape with one pair of charge–discharge voltage plateau, which is similar to the results of CV test (Fig. 4b and c). And the specific capacity is 342 F g⁻¹ at a current density of 2 A g⁻¹, it is approximately equivalent to the 345 F g⁻¹ at a scan rate of 20 mV s⁻¹. Next, the specific capacitance of our juglone nanowire is further compared to those of the reported conventional electrode materials.^45–51 As shown in Fig. 4d, the capacity of N/rGO (reduced graphene oxide doping with nitrogen) is 138 F g⁻¹, and our juglone nanowire have about 2-fold higher specific capacity than N/rGO, 1.5-fold higher than Fe₃O₄/rGO (154 F g⁻¹).Open in a separate windowFig. 4(a) CV curves of the juglone nanowire electrode at different scan rates from 10 mV s⁻¹ to 100 mV s⁻¹. (b) Charge and discharge curves in the current density range from 2 A g⁻¹ to 10 A g⁻¹. (c) Various specific capacity of the juglone nanowire electrode when increasing the scan rate from 10 mV s⁻¹ to 200 mV s⁻¹. (d) Specific capacity of juglone nanowire in comparison with different materials.     

我国公立医院医疗服务支付制度改革进展及存在问题探讨

在梳理我国公立医院医疗服务支付制度历史沿革、主要改革做法及成效的基础上,重点分析改革中存在的支付标准不够科学合理、支付制度改革缺乏系统性和联动性、医务人员参与改革的积极性未能充分调动等问题及深层次的制度原因,进而提出推进我国公立医院医疗服务支付制度改革的政策建议,包括谈判确定支付标准,创新支付方式改革的“组合拳”,逐步推进支付制度改革系统工程,建立支付制度改革激励作用的传动机制.     

The Impaired Function of Macrophages Induced by Strenuous Exercise Could Not Be Ameliorated by BCAA Supplementation

The aim of this study was to evaluate the effect of strenuous exercise on the functions of peritoneal macrophages in rats and to test the hypothesis that branched-chain amino acid (BCAA) supplementation will be beneficial to the macrophages of rats from strenuous exercise. Forty male Wistar rats were randomly divided into five groups: (C) Control, E) Exercise, (E1) Exercise with one week to recover, (ES) Exercise + Supplementation and (ES1) Exercise + Supplementation with 1 week to recover. All rats except those of the sedentary control were subjected to four weeks of strenuous exercise. Blood hemoglobin, serum testosterone and BCAA levels were tested. Peritoneal macrophages functions were also determined at the same time. The data showed that hemoglobin, testosterone, BCAA levels, and body weight in group E decreased significantly as compared with that of group C. Meanwhile, phagocytosis capacity (decreased by 17.07%, p = 0.031), reactive oxygen species (ROS) production (decreased by 26%, p = 0.003) and MHC II mRNA (decreased by 22%, p = 0.041) of macrophages decreased in the strenuous exercise group as compared with group C. However, the chemotaxis of macrophages did not change significantly. In addition, BCAA supplementation could slightly increase the serum BCAA levels of rats from strenuous exercise (increased by 6.70%, p > 0.05). Moreover, the body weight, the blood hemoglobin, the serum testosterone and the function of peritoneal macrophages in group ES did not change significantly as compared with group E. These results suggest that long-term intensive exercise impairs the function of macrophages, which is essential for microbicidal capability. This may represent a novel mechanism of immunosuppression induced by strenuous exercise. Moreover, the impaired function of macrophage induced by strenuous exercise could not be ameliorated by BCAA supplementation in the dosing and timing used for this study.     

Dietary nucleotides supplementation during the suckling period improves the antioxidative ability of neonates with intrauterine growth retardation when using a pig model

The aim of the present study was to investigate the effect of dietary nucleotides supplementation on the antioxidant status of piglets affected by intrauterine growth retardation (IUGR). Fourteen pairs of normal birth weight (NBW) and IUGR piglets were fed either a control diet (CON) or a nucleotides supplementation diet (NT) from 7 d of age to 28 d postnatal. Blood, liver and jejunum samples were collected at the end of the study. The results showed that IUGR piglets had decreased (P < 0.05) concentrations of plasma total antioxidant capability (T-AOC) and total superoxide dismutase (T-SOD), gene expressions of hepatic cytoplasmic copper/zinc SOD (CuZnSOD) and PPARγ coactivator-1α (PGC-1α) and jejunal glutathione peroxidase (GP_X) and extracellular superoxide dismutase (ESOD), accordingly, there was markedly higher (P < 0.05) plasma malondialdehyde (MDA) and hepatic and jejunal mitochondria DNA content in the IUGR piglets relative to NBW piglets. Regardless of body weight, dietary NT supplementation significantly increased (P < 0.05) plasma concentrations of T-AOC, T-SOD, CuZnSOD, GP_X and the ratio of reduced glutathione to oxidized glutathione, hepatic T-SOD, GP_X and mitochondria DNA content, while hepatic MDA concentration was markedly decreased (P < 0.05) 19.1% by NT diet. Furthermore, the gene expressions of hepatic glutathione reductase, CuZnSOD, nuclear erythroid 2-related factor 2, PGC-1α and nuclear respiratory factor-1 (NRF-1) and jejunal GP_X, CuZnSOD, ESOD and NRF-1 were significantly increased (P < 0.05) by NT diet, whereas the gene expression of Kelch-like ECH-associated protein 1 were markedly decreased (P < 0.05) compared with that of piglets fed with CON diet. These results indicate that dietary NT supplementation prevents the effect of IUGR on oxidative status and mitochondria DNA damage through improving the non-enzymatic and enzymatic antioxidant capacities as well as mitochondria biogenesis of piglets.

The aim of the present study was to investigate the effect of dietary nucleotides supplementation on the antioxidant status of piglets affected by intrauterine growth retardation (IUGR).     

Enhancing the mechanical performance of poly(ether ether ketone)/zinc oxide nanocomposites to provide promising biomaterials for trauma and orthopedic implants

Poly(ether ether ketone)/zinc oxide (PEEK/ZnO) composites were manufactured by using the injection molding technique. Before blending with the PEEK resin matrix, some ZnO nanoparticles were modified by γ-aminopropyltriethoxylsilane (APTES). The effect of surface modification of ZnO nanoparticles by amino groups and Si–O bonds was investigated. PEEK/ZnO composites were characterized by scanning electron microscopy (SEM), thermogravimetric analysis, and X-ray diffraction. The scanning electron micrographs showed that ZnO nanoparticles were encapsulated in the PEEK phase; within this phase, the nanoparticles were homogeneously dispersed. Mechanical and tribological properties were measured by tensile strength, flexural strength, coefficient of friction, and wear rate. It was shown that the interfacial compatibility between ZnO nanoparticles and PEEK matrix was significantly enhanced due to the amino and Si–O bonds decorated on the ZnO nanoparticles. More importantly, the thermal stability of PEEK improved upon the incorporation of ZnO nanoparticles into this matrix. Cell viability studies with mouse osteoblasts demonstrated that cell growth on PEEK and PEEK/ZnO was significantly enhanced. On the basis of the obtained results, PEEK/ZnO composites are recommended as promising candidates for orthopaedic materials and trauma implants.

Poly(ether ether ketone)/zinc oxide (PEEK/ZnO) composites were manufactured by using the injection molding technique.