Enhancement of gastrointestinal absorption of isoliquiritigenin by nanostructured lipid carrier

Isoliquiritigenin (ISL) has various pharmacological effects. Our previous studies demonstrated that the oral bioavailability of ISL was low and the concentration-time profiles of ISL exhibited double peaks after oral administration in rat, but the underlying mechanisms remained unknown. The objective of this study was to clarify the gastrointestinal (GI) absorptive characteristics of ISL using in situ intestinal perfusion model as well as explain double peaks phenomenon after oral administration and to evaluate the potential of using nanostructured lipid carrier (NLC) as an oral delivery carrier for poorly water soluble drugs. The results showed that the absorption percent in the stomach for 2 h was less than 10%, the absorption process of intestine was first-order process with passive diffusion mechanism, and the main absorptive segment was colon. Isoliquiritigenin-loaded nanostructured lipid carrier (ISL-NLC) could enhance oral absorption of ISL. The reason for the Double Peak Phenomenon following oral administration in ISL plasma concentrations versus time profiles is Variability of Absorption within different regions of the gut, very low absorption from the stomach, jejunum, duodenum and ileum compared with the absorption from the colon. A pharmacokinetic study was conducted in rats after a single dose oral administration of ISL at 20 mg/kg in the form of either ISL-NLC or isoliquiritigenin solution (ISL-Sol). The AUC _(0∼∞) values were 5.43 ± 0.67 μg h mL⁻¹ and 29.60 ± 2.88 μg h mL⁻¹ after administration of the ISL-Sol and ISL-NLC, respectively. The relative bioavailability of ISL-NLC to isoliquiritigenin was 545%. Our studies provide evidence that NLC are valuable as an oral delivery carrier to enhance the absorption of a poorly water soluble drug, ISL.     

异甘草素合成工艺优化及其清除自由基活性研究

对异甘草素的合成工艺进行优化和体外清除自由基活性进行研究。通过间苯二酚、冰醋酸、对羟基苯甲酸合成异甘草素,考察物料比、温度、反应时间对产率的影响,通过紫外分光度法对其清除自由基活性进行研究。酚与酸物料比1∶2.5,240 W微波辐射3 min,2,4-二羟基苯乙酮产率最高为65.75%;当醛酮物质的量比为3∶1,温度控制在120~130℃,回流6 h,异甘草素产率最高为28.10%;反应时间控制20 min,异甘草素加入量为1.00 m L清除DPPH自由基能力最强,为66.4%。异甘草素具有一定的抗自由基活性。     

Development of sample preparation method for isoliquiritigenin,liquiritin, and glycyrrhizic acid analysis in licorice by ionic liquids-ultrasound based extraction and high-performance liquid chromatography detection

An ionic liquid-based ultrasonic-assisted extraction (ILUAE) method had been used for the effective extraction of isoliquiritigenin (IQ), liquiritin (LQ) and glycyrrhizic acid (GA) from licorice. The ionic liquids with different cations and anions were investigated in this work and 0.5 M 1-butyl-3-methylimidazolium bromide solution was selected as solvent. In addition, the technical parameters including soaking time, solid–liquid ratio, ultrasonic power and time were optimized. Compared with the conventional solvent extraction, the proposed approach exhibited higher efficiency, which indicated the ILUAE was an efficient, rapid and simple sample preparation technique. There was no degradation of the target analytes had been observed at the optimum conditions which was evidenced by the stability studies performed with standard of IQ, LQ and GA. The proposed method also showed high reproducibility and was environmental friendly.     

Shallot and licorice constituent isoliquiritigenin arrests cell cycle progression and induces apoptosis through the induction of ATM/p53 and initiation of the mitochondrial system in human cervical carcinoma HeLa cells

This study is the first to investigate the anticancer effect of isoliquiritigenin (ISL) in human cervical carcinoma HeLa cells. The results reveal that ISL inhibits HeLa cells by blocking cell cycle progression in the G2/M phase and inducing apoptosis. Blockade of cell cycle is associated with increased activation of ataxia telangiectasia‐mutated (ATM). Activation of ATM by ISL phosphorylated p53 at Serine15, resulting in increased stability of p53 by decreasing p53 and murine double minute‐2 (MDM2) interaction. In addition, ISL‐mediated G2/M phase arrest was also associated with decreases in the amounts of cyclin B, cyclin A, cdc2, and cdc25C, and increases in the phosphorylation of Chk2, cdc25C, and cdc2. The specific ATM inhibitor caffeine significantly decreased ISL‐mediated G2/M arrest by inhibiting the phosphorylation of p53 (Serine15) and Chk2. ISL induced apoptotic cell death is associated with changes in the expression of Bax and Bak, decreasing levels of Bcl‐2 and Bcl‐X_L, and subsequently triggering mitochondrial apoptotic pathway. In addition, pretreatment of cells with caspase‐9 inhibitor blocked ISL‐induced apoptosis, indicating that caspase‐9 activation is involved in ISL‐mediated HeLa cell apoptosis. These findings suggest that ISL may be a promising chemopreventive agent against human uterine cervical cancer.     

异甘草素键合硅胶固定相的合成及应用

以10μm硅胶为基质,异甘草素为配体,采用液相连续反应法及中间体法依次合成了异甘草素键合硅胶固定相ISLSP-Ⅰ和ISLSP-Ⅱ。采用FTIR及SEM对合成的固定相进行表征。将ISLSP-Ⅰ固定相填充于50 mm×10 mm i.d. 1号色谱柱中,将ISLSP-Ⅱ固定相填充于30 mm×10 mm i.d. 2号色谱柱中,系统评价了两种方法合成的固定相的色谱性能。结果表明:两根色谱柱的柱效及峰型均较好,大流速下测试组分的保留主要决定于传质阻力。在甲醇-水体系下,2号色谱柱表现出明显的反相色谱分离机制。合成的固定相稳定性良好,使用6个月后,测试组分在两根色谱柱上的保留时间相对偏差不超过0.9%。2号色谱柱对多组分标准样品及中药提取物均具有良好的分离能力。