The Self-Assembly Soluplus Nanomicelles of Nobiletin in Aqueous Medium Based on Solid Dispersion and Their Increased Hepatoprotective Effect on APAP-Induced Acute Liver Injury.

Purpose: APAP-induced liver injury (AILI) is a common cause of acute liver failure (ALF). Nobiletin (NOB) is a potential hepatoprotective agent for the treatment of APAP-induced liver injury. However, the poor solubility and low bioavailability of NOB hinders its application. In this study, a novel self-assembly nano-drug delivery system of nobiletin (solid dispersion of NOB, termed as NOB/SD) was developed based on solid dispersion technology to improve the bioavailability and hepatoprotective ability of NOB for APAP-induced liver injury therapy. Methods: The optimized NOB/SD system was constructed using the amphiphilic copolymers of Soluplus and PVP/VA 64 via hot melt extrusion technology (HME). NOB/SD was characterized by solubility, physical interaction, drug release behavior, and stability. The bioavailability and hepatoprotective effects of NOB/SD were evaluated in vitro and in vivo. Results: NOB/SD maintained NOB in matrix carriers in a stable amorphous state, and self-assembled NOB-loaded nanomicelles in water. Nanostructures based on solid dispersion technology exhibited enhanced solubility, improved release behavior, and promoted cellular uptake and anti-apoptosis in vitro. NOB/SD displayed significantly improved bioavailability in healthy Sprague Dawley (SD) rats in vivo. Furthermore, NOB/SD alleviated the APAP-induced liver injury by improving anti-oxidative stress with reactive oxygen species (ROS) scavenging and nuclear factor erythroid 2-related factor 2 (Nrf2) activation. Conclusion: These results suggested that NOB/SD could be considered as a promising hepatoprotective nano-drug delivery system for attenuating APAP-induced acute liver injury with superior bioavailability and efficient hepatoprotection, which might provide an effective strategy for APAP-induced acute liver injury prevention and treatment.

Qualitative and Quantitative Analyses of the Chemical Components of Peels from Different Pomelo Cultivars (Citrus grandis [L.] Osbeck) Based on Gas Chromatography-Mass Spectrometry, Ultraperformance Liquid Chromatography-Q-Exactive Orbitrap-MS, and High-Performance Liquid Chromatography-Photodiode Array Detection.

The volatile and nonvolatile phytochemicals in peels of 5 major pomelo cultivars (including Citrus grandis cv. Yuhuanyou, C. grandis cv. Liangpingyou, C. grandis cv. Guanximiyou, C. grandis cv. Duweiwendanyou, and C. grandis cv. Shatianyou) from 11 places in China were characterized. First, 194 volatile compounds in pomelo peels were identified by gas chromatography-mass spectrometry (GC-MS). Of these, 20 major volatile compounds were subjected to cluster analysis. The heatmap indicated that the volatile compounds in peels of C. grandis cv. Shatianyou and C. grandis cv. Liangpingyou were different from those in other varieties, while there was no difference among C. grandis cv. Guanximiyou, C. grandis cv. Yuhuanyou, and C. grandis cv. Duweiwendanyou from different origins. Second, 53 nonvolatile compounds were identified in pomelo peels by ultraperformance liquid chromatography-Q-exactive orbitrap tandem MS (UPLC-Q-exactive orbitrap-MS), of which 11 components were detected for the first time. Third, six major nonvolatile compounds were quantitatively analyzed with high-performance LC-photodiode array detection (HPLC-PDA). Combining the results of HPLC-PDA and the heatmap, 6 nonvolatile compounds in 12 batches of pomelo peel were well separated among varieties. Comprehensive analysis and identification of chemical components in pomelo peels are of great significance for their further development and utilization.

Comparative analysis of chemical constituents in Citri Exocarpium Rubrum, Citri Reticulatae Endocarpium Alba, and Citri Fructus Retinervus.

Citri Exocarpium Rubrum (CER), Citri Reticulatae Endocarpium Alba (CREA), and Citri Fructus Retinervus (CFR) are used as medicine and food, which derive from three different parts of the pericarp of Citrus reticulata Blanco through natural drying. To systematically investigate similarities and differences in phytochemicals about the three herbs, a series of analytic approaches were applied for the qualitative and quantitative analysis of chemical constituents in them. The results indicated a total of 48 volatile compounds were determined representing 99.92% of the total relative content of CER extracts, including 24 alkenes, 11 alcohols, 6 aldehydes, 2 ketones, and 2 phenols, while volatile compounds were not extracted from CREA and CFR. CER was abundant in volatile components that mainly existed in the oil gland. And a total of 32, 35, and 28 nonvolatile compounds were identified from CER, CREA, and CFR extracts, respectively. The total content of flavonoids and phenolic, and hesperidin in CFR was the highest, followed by CREA and CER. Conversely, CER was a rich source of polymethoxyflavones (PMFs), and the total polymethoxyflavone content (TPMFC), the content of nobiletin, 3,5,6,7,8,3',4'-heptamethoxyflavone (HMF), tangeretin, and 5-hydroxy-6,7,8,3',4'-pentamethoxyflavone (5-HPMF) in CREA and CFR were extremely low. Besides, CER and CREA had a higher concentration of synephrine than CFR. The phytochemicals of CER, CREA, and CFR were significantly different, which might provide chemical evidence for the comparative pharmacological activities' research and rational application of them.

Qualitative and quantitative analyses of chemical components of Citri Sarcodactylis Fructus from different origins based on UPLC-Q-Exactive Orbitrap-MS and GC-MS.

Ultra-high-performance liquid chromatography-Q-Exactive Orbitrap-mass spectrometry (MS) and gas chromatography (GC)-MS were performed for the qualitative and quantitative analyses of Citri Sarcodactylis Fructus (CSF) from different origins. The contents of eight major CSF components, namely 5,7-dimethoxycoumarin, scopoletin, hesperidin, tangeretin, nobiletin, limonin, nomilin, and stachydrine, were quantitatively analyzed. Clustering analysis and principal component analysis (PCA) were, respectively, performed to classify and compare the 10 CSF batches. One hundred and two volatile components were identified accordingly by comparing retention times, reference standards, parent peaks, fragment peaks, and findings from relevant literature. Moreover, high content of 5,7-dimethoxycoumarin and stachydrine was detected in all the CSFs, especially in CSF-Zhe. Therefore, the high content component coumarin "5,7-dimethoxycoumarin" was suggested to be quality analysis component rather than hesperidin. Additionally, characteristic compounds were found to distinguish different CSFs. This work was a comprehensive study about the components of various CSF. It distinguished the basic differences in the compositions of CSF from different origins. Eventually, it provided experimental and systematic bases for the quality control analysis of CSF, which has potential application in the further research.

Analysis of the chemical components of pomelo peels (Citrus grandis [L.] Osbeck) from different cultivars by using supercritical CO2 fluid extraction and ultra-high-performance liquid chromatography-tandem mass spectrometry.

Five pomelo cultivars (i.e., Citrus grandis cv. Shatianyou, Citrus grandis cv. Guanximiyou, Citrus grandis cv. Yuhuanyou, Citrus grandis cv. Duweiwendanyou and Citrus grandis cv. Liangpingyou) from different origins in China were selected to analyze their components by using supercritical CO2 fluid extraction coupled with ultra-high-performance liquid chromatography-tandem mass spectrometry. A total of 45 compounds were identified in the supercritical CO2 fluid extracts of the pomelo peels from the five cultivars. These compounds included eight flavonoids, 18 coumarins, four organic acids, three aldehydes, and 12 other compounds, which were identified using the obtained MS data and by comparison with commercial standards, orbitrap Chinese Traditional Medicine Library, and previous literature. Twenty-five of the identified compounds were detected for the first time in the pomelo peel extracts. Results suggested that the pomelo peels of C. grandis cv. Shatianyou contained the most natural chemical compositions. The pooled result may offer scientific evidence for further development and utilization of pomelo peels and a route for screening appropriate varieties for various demands.