The flavin-containing monooxygenase (FMOs) is recognized as an important complimentary enzyme system next to the cytochrome P450 (CYP450), which catalyzes the metabolism of many xenobiotics (nucleophilic heteroatom-containing chemicals) and several endobiotics. This article provides a comprehensive introduction of FMOs including the biological characteristics, catalytic mechanism, substrate specificity, genetic polymorphisms. The effect of FMOs on drug metabolism and individual differences and relation with diseases are also mentioned. It is valuable for the discovery of therapeutic targets and design of new drug candidate.

Differences of the individual toxic effects of antitumor drugs have been a concern in clinical treatment of cancers. The drug toxicity was not only related to the age, sex, and drug interactions, but also to the expression of protein involved in the metabolism, targets and transporters of drugs. Drug transporter mediates the absorption, distribution and elimination of some drugs, which exhibits a great significance in pharmacology and clinical practice. The purpose of this review is to provide information regarding trans-porter-medicated toxic effects of antitumor drugs in order to reduce or avoid the transporter-medicated toxic effects, and to promote reasonable drug use and individualized application of antitumor drugs in clinics.

Calcium-activated chloride channel (CaCC) is an anion channel, widely distributed in the human body, taking a part in cell functions including secretion, heart muscle repolarization, nerve signal transmission and several physiological activities. The anoctamin 1 (ANO1) protein is the molecular basis of CaCC and the modification of ANO1 protein will produce a variety of pharmacological effects, such as analgesia, treating dysentery and asthma, even tumor proliferation and migration inhibition. In the past decade, many methods in screening of ANO1 regulators have been developed. Although a series of the ANO1-based CaCC regulatory molecules have been identified, the pharmacological effects of these molecules are not consistent. In this review, we introduce ANO1 protein regulators from many aspects including bio-test methods, structure-activity relationships, and the potential applications.

Microfluidics is a technology that involves the use of micro-nanoscale pipelines to manipulate fluid mixing. Precise control of the mixing process of laminar flows or liquid droplets by using microfluidics will contribute to the preparation of nanoparticles, which are difficult to be achieved by the conventional methods. Based on the progress in delivery systems of nanoparticulate drug, we provide a summary to introduce the applications of microfluidics in construction of nanoparticulate drug delivery system such as liposomes, polymer nanoparticles and hybrid nanoparticles, and analyze the assembling mechanisms of different nanostructures by using microfluidic precise control. This review will provide a reference in utilization of microfluidic technology more scientifically and reasonably.

Anthocyanins has a high health benefits and biological activity, which can make the solution easily absorbed and has a bright color, beautiful appearance in oral liquid. However, due to its particularity antioxidant activity, it is easy to be affected by the external physical and chemical factors, and then oxidation, polymerization, degradation and other unstable phenomena occurs that seriously affect the stability of products and shelf life. The traditional methods of pH regulation, deoxygenation and light avoidance could not meet the demand of stable anthocyanins. Addition of stabilizer to anthocyanins is a new effective way to improve the stability of anthocyanins. This paper is prepared to summarize systematically the principle and application methods of anthocyanins stabilizers to explore the key technology of clarification and stabilization of traditional Chinese medicine in the natural oral liquid, which may provide theoretical support and technical reference for the development and utilization of anthocyanins stabilizer.

The study is designed to evaluate the protective effect of xanthan gum (XG) injection on cartilage injury in the rabbit osteoarthritis (OA) model induced by anterior cruciate ligament transection (ACLT), and to explore the effect of XG on the expression of caspase-3 and Bax protein in OA cartilage. Sixty male New Zealand white rabbits were randomly divided into 6 groups (n=10) according to random number table method, and one group was selected randomly as the normal control group (control) while the other 5 groups of right knee were used to establish the OA model with ACLT, which were then divided into model group (model), XG-0.6 mg·kg^-1, XG-1.2 mg·kg^-1, XG-2.4 mg·kg^-1 treatment group and sodium hyaluronate (SH-1.2 mg·kg^-1) treatment group according to drug intervention. The knee joint temperature and knee joint width of each group were measured in the course of treatment. After treatment, the macroscopic morphology of rabbit joints in each group was observed. The pathological morphology of articular cartilage of rabbits in each group was observed using HE staining. The expression of Bax and cleaved caspase-3 in the cartilage of rabbits were detected by Western blot. The result shows that XG inhibited the increase in knee joint temperature and knee width caused by OA in a dose-dependent manner. XG improved the morphological abnormalities and tissue injuries of the femoral condyle and tibial plateau caused by OA. Western blot result shows that, compared with the control group, the levels of Bax and cleaved caspase-3 in knee cartilage cells of model group and XG-0.6 mg·kg^-1 group were significantly increased (P < 0.01). However, no significant difference was observed in the levels of Bax and cleaved caspase-3 between the model group and the XG-0.6 mg·kg^-1 group (P>0.05). These two groups are significantly higher than those of XG-1.2 mg·kg^-1 and XG-2.4 mg·kg^-1 (P < 0.01) groups. Meanwhile, no significant difference was observed in the level of cleaved caspase-3 between the knee cartilage in XG-2.4 mg·kg^-1 and XG-1.2 mg·kg^-1 group (P>0.05). The level of Bax in knee cartilage in XG-2.4 mg·kg^-1 group was lower than that of XG-1.2 mg·kg^-1 group (P < 0.05). In conclusion, XG effectively protected cartilage damage in OA, and inhibited the expression of Bax and caspase-3 protein in OA cartilage.

To study the effects of squalene on behavior and related proteins of glutamate toxicity pathways in the mice with chronic unpredictable mild stress (CUMS), thirteen different kinds of CUMS were applied to the male BALB/C mice for 35 days to establish the mouse model of CUMS depression. The stress conditions include food deprivation, noise, stroboscopic lighting, hot stress (45℃), brake, exposure to lower temperature (4℃), shake, soiled cage, clamp tail, water deprivation, swimming, electric shock, presence of a foreign object in the home cage. The mice were treated with squalene at 3 doses (80, 40 and 20 mg·kg^-1·d^-1) through oral administration from the 3rd week continuously. Three weeks later, the impacts were evaluated in the mice with behavioral tests, and malondialdehyde (MDA) and hippocampal glutamate (GLU) contents, the superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity in hippocampus were measured by spectropho-tometry or reversed phase HPLC (RP-HPLC). Western blot was used to examine the expression level of N-methyl-D-aspartate receptor subunits epsilon-2 (NMDAε2), calmodulin kinaseⅡ (CaMKⅡ) and neuronal nitric oxide synthase (NOS1) in hippocampus. Compared with model group, the squalene-treated mice exhibited an increase in body weight, sucrose preference rate and the times of crossing-movement and rearing-movement, shortened the immobility time in the tails suspension test and forced swimming test in the depression mice (P < 0.05). Meanwhile, the treated mice had a significant decrease in the contents of GLU and MDA (P < 0.05) in hippocampus, increased the activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and downregulated the expression of NMDAε2, CaMKⅡ and NOS1 in the hippocampus. In conclusion, squalene shows anti-depressant effect on depressant model in mice, meanwhile the downregulated ROS, related proteins of GLU-NMDAε2-CaMKⅡ-NOS1 signal pathways may be related to the antidepressant effect of squalene.

The study was designed to test the role of 5, 2', 4'-trihydroxy-6, 7, 5'-trimethoxy flavone nanoparticle (TTF1-NP) on lipopoiysaccharide (LPS)-induced inflammatory response, and to explore the anti-inflammatory mechanism in human hepatocellular carcinoma cells. Inflammatory responses were induced in human hepato-cellular carcinoma HepG2 cells with LPS; Proliferation effect of TTF1-NP in LPS-stimulated HepG2 cells were detected by MTT assay; The expression of TLR4, AKT/mTOR signaling related proteins and IL-6 were detected by Western blot assay. The results showed that TTF1-NP inhibited the proliferation of HepG2 cells induced by LPS in a dose-dependent manner; TTF1-NP inhibited the expression of TLR4, the activation of AKT and mTOR, and expression of IL-6 in a dose-dependent manner; TTF1-NP inhibited the activation of AKT/mTOR signaling pathway and TLR4 proteins leading to suppression of IL-6 expression in HepG2 cells stimulated by insulin. These results suggest that TTF1-NP inhibited inflammatory responses from LPS treatment with a potential mechanisms in the inhibition of AKT/mTOR pathway.

This study was designed to investigate the molecular mechanism and potential active constituents of Polygala Radix in the treatment of Alzheimer's disease with multiple data bases combined with literature mining to build Polygala Radix chemical composition database. A novel analysis tool Pharmmapper was used to obtain the main active ingredient and potential target of Polygala Radix. By extensive data profiling, the Polygala Radix was found to contain 111 chemical constituents. Among them, a total of 10 active molecules included 3 xanthone, 1 saponins, 3 oligosaccharide esters, and 3 other classes were related to 13 Alzheimer's disease-related targets. Two of the core targets were beta-secretase 1 and glycogen synthase kinase-3 beta. Use the GO analysis and KEGG to explore the molecular mechanism of Polygala Radix in treatment of Alzheimer's disease, which has 3 signaling pathways, and the most important signaling pathway is the cell death signaling pathway. The active constituents of Polygala Radix could control the formation of Aβ and the apoptosis of cells through the interaction with multiple targets, and control the treatment of Alzheimer's disease.

To investigate the effects of metformin on pancreatic β-cell function and its possible mechanism, high fat diet-induced type 2 diabetic C57BL/6J mice were divided into two groups according to fasting blood glucose (FBG), glucose decreasing rate at 40 min of insulin tolerance test, triglycerides (TG), cholesterol (CHO) and body weight (BW). The C57 mice were gavaged with water or metformin for 58 days. β-Cell function was evaluated by oral glucose tolerance test and hyperglycemic clamp. Genes and proteins related to pancreas proliferation, lipid metabolism and endoplasmic reticulum stress were investigated. Compared with the model group, metformin group exhibited a reduction in the body weight (P < 0.01), plasma TG and CHO (P < 0.05), and the area under the curve (AUC) (P < 0.05) of glucose tolerance test. The glucose infusion rate during clamp was improved (P < 0.05) and the fasting insulin level was decreased in the metformin group (P < 0.05). Metformin significantly upregulated the gene expression of pancreatic and duodenal homeobox 1 (Pdx-1, P < 0.01) and liver X receptor β (Lxr-β, P < 0.01). Western blot results showed that, the protein expression of PDX-1 was significantly upregulated (P < 0.01). Endoplasmic reticulum stress related protein of activating transcription factor 4 (ATF4, P < 0.001) and C/EBP homologous protein (CHOP, P < 0.05) were also down-regulated. These results suggest that metformin could improve the insulin secretion function of type 2 diabetic C57BL/6J mice. The mechanism of the action may rely on its improvement of pancreas cell proliferation, lipid metabolism and amelioration of endoplasmic reticulum stress.

Bromodomain-containing proteins (BCPs) can specifically recognize acetylated lysine (KAc) in histones and other substrate proteins. Recently, several kinase inhibitors were found to inhibit bromodomains, such as the PLK1 inhibitor BI-2536 and the JAK2 inhibitor TG101209, which bind to BRD4 with IC₅₀ values of 25 nmol·L^-1 and 130 nmol·L^-1, respectively. To obtain potent BRD4 inhibitors from inhibitor BI-2536, we used dihydroquinoxalin-2(1H)-one to replace the 7, 8-dihydropteridin-6(5H)-one in BI2536. By exploring the structure-activity relationships of the new dihydroquinoxalin-2(1H)-one structures, we obtained a novel phenyl side chain series of BRD4 inhibitors. We identified several potent BRD4 inhibitors, especially compounds 16, 22, 28 and 29, which had IC₅₀ values below 100 nmol·L^-1 in fluorescence anisotropy (FA) assays, indicating this series of compounds are worth to fruther investigation.

The protein-protein interactions play an important role in life science. At present, many methods are developed with preferences of the amino acid residues, which do not offer the relative spatial information for the residue groups. However, the spatial information for the residue groups is important in the design of the protein-protein interactions. We proposed a new model, which is named 'tri-prism' model, by deep mining the existing protein-protein interaction patterns and refining the preference and the relative spatial information for the combination pairs of the residue groups. The model not only provided the preferences, but also offered the relative spatial information for the triplets combination pairs of the residue groups. The model was able to analyze the triplets combination pairs of the residue groups based on the preference factor, amino acid composition, and protein secondary structure. The model was applied to the interface of the PD-1/PD-L2 protein. According to the diversity characters of the composition and the spatial information between the combination pairs of the residue groups at the interface of the PD-1/PD-L2 protein and the predicted ones, we put forward the suggestions for the mutations of the residues, which offered a new view in the study of protein-protein interactions.

The study aims to establish an LC-MS/MS method for the determination of S-(+)-ibuprofen (S-IBP) and R-(-)-ibuprofen (R-IBP), which may be used subsequently to investigate the pharmacokinetics of ibuprofen enantiomers in healthy Chinese volunteers. Naproxen was used as an internal standard. The separation was achieved on a Chiralpak AD-3R column (4.6 mm×150 mm, 3.0 μm) with a mobile phase consisting of acetonitrile/0.01% formic acid aqueous solution (40:60) at a flow rate of 750 μL·min^-1 within 23.0 min. Naproxen and the internal standard were measured by a triple-quadrupole mass spectrometer in negative electron electronic spray ion (ESI) mode using multiple reaction monitoring (MRM). The extracted ions monitored following MRM transitions were m/z 205.1→161.0 for ibuprofen enantiomers and m/z 229.1→185.0 for the internal standard naproxen. Plasma samples were pretreated through methanol precipitation. The calibration curve of S-IBP and R-IBP in human plasma was linear over the concentration rang of (0.05-30.00) μg·mL^-1. The lower limit of quantitation was 0.05 μg·mL^-1. The intra-and inter-run precisions of S-IBP at three quality control levels were within 2.2%-4.2%, the relative deviation of the assay was within -12.0%-13.0%. The intra-and inter-run precisions of R-IBP at three quality control levels were within 2.0%-8.2%, the relative deviation of the assay was within -11.5%-10.6%. The plasma samples were stable at room temperature (25℃) for 6 h, at -30℃ for 47 days and during three freeze-thaw cycles. The method was proved to be convenient, accurate and sensitive, and suitable for the pharmacokinetics study of ibuprofen enantiomers in healthy Chinese volunteers after a single oral dose of 300 mg ibuprofen extended-release capsule.

Using a UHPLC-TOF/MS method combined with software of Masslynx V4.1 and database in the literatures, a total of 20 polygala oligosaccharide esters (POEs) were identified in 60% ethanol extract of Kai Xin San (KXS-60%E). Furthermore, 14 POEs as well as 4 POE-metabolites were identified in rat plasma. The results revealed that POEs and POE-metabolites which were identified in rat plasma, were key components in KXS-60%E and the potential bioactive compounds for KXS action in the treatment of AD.

Due to the characteristics of propofol of high time-varying, and complex compartment model, the traditional method of nonlinear mixed effects modeling (NONMEM) has miscellaneous of variables and plenty of artificial factors in the estimation of propofol. This study was aimed to build a propofol prediction model based on the differential evolution (DE) algorithm and grey model. DE was used to optimize the pa-rameter of multi-variable grey model (MGM) and to build a model of prediction of the plasma concentration of propofol based on the grey model. It was compared with the results of NONMEM algorithm. In conclusion, the median performance error (MDPE) of DE-MGM was -4.6%, while the result of NONMEM is -12.13%. The median absolute performance error (MDAPE) of GA-BP neural network is 13.19%, while that of NONMEM is 23.12%. The experimental results suggest that the new method is suitable to determine the short half-life of anesthesia drug propofol with higher accuracy.

Charge-reversal nanocarrier was constructed to enhance lysosomal escape and improve an-titumor effect. We synthesized the cholesterol-polyethyleneimine-hexahydrophthalic anhydride (Chol-PEI-HHPA) polymer and characterized by ¹H NMR. The charge-reversal liposomes (Lipo-HHPA) were synthesized and the hematoporphyrin monomethyl ether (HMME) was loaded. pH-triggered charge conversion was determined at different pH values. The lysosomal escape and cytotoxicity of the Lipo-HHPA were evaluated in MCF-7 cells. The Lipo-HHPA was uniform with an average particle size of 102 nm. Upon the irradiation of ultrasound, burst release of HMME could be observed. The zeta potential of Lipo-HHPA changed sharply from negative (-23.5 mV) to positive (+21.2 mV) over the pH range of 7.4-4.5. In the cellular uptake experiment, the lysosomal escape of Lipo-HHPA was observed. HMME loaded Lipo-HHPA displayed obviously enhanced cytotoxicity towards MCF-7 cells. These results indicate that the charge-reversal liposomes hold a great potential in improving the cytotoxicity and antitumor effect.

Based on the principle of particle design, the powder of Xiaojin Pills was prepared, and the quality uniformity was investigated by means of powder characterizations and content uniformity. By studying the mixed crushing rules of the classified materials and the design principle of the powder particles of Chinese medicine, the powder of the Xiaojin Pills was prepared. At the same time, the manmade mixed powder and the control powder prepared by pharmacopoeia were prepared. The mixed homogeneity of the three powders was evaluated by particle size distribution and color difference. The GC-MS and LC-MS/MS were used to study the homogeneity of their contents. The best preparation process of particle design powder is:materials easily crushed are smashed for 50 min in the vibrating ultrafine mill with -15℃, then add the materials difficultly crushed into the mill and let them crushed together for 3 min. The particle size range of manmade mixed powder was the largest with the particle size difference being more than 100 microns, the RSD value being 26.07%. The particle size range was more than 50 microns in the powder prepared by pharmacopoeia, and the RSD was nearly 15%. The difference in particle size was only around 4 μm and the RSD value was 3.18%. The color difference test showed that the composite chromatism (dE^*) value of the powder prepared by pharmacopoeia was the largest for the RSD was 84.56%. The RSD of manmade mixed powder and the powder prepared by Pharmacopeia were 53.83% and 32.83%, respectively. The RSD value of the particle designed powder's muscone content is about 50% of the other two kinds of powders. The contents of 10 components in powders were determined by LC-MS/MS. The RSD values of the particle designed powder were much smaller than other two kinds of powders. Results indicate that the uniformity of the particle designed powder is better than other two kinds of powders. Chinese medicine particle design technology can effectively improve the uniformity of traditional Chinese medicine powder.

Rubia cordifolia L. has been used as a traditional Chinese medicine for several centuries. In recent years, the resources of wild Rubia cordifolia have been declined sharply due to increased utilization and rising price. Therefore, it is of great urgency to evaluate and protect resources of wild plant of Rubia cordifolia. In our study, sixty-four individuals that represent eight wild populations of Rubia cordifolia L. were analyzed by Start Codon Targeted Polymorphism (SCoT) molecular markers. Genetic distance was calculated by POPGENE 3.2 software, cluster analysis was generated by NTSYS 2.10 software based on UPGMA method and Mantel Test was used to analysis the relationship between the genetic distances and geographical distance among the wild populations. The results showed a high genetic diversity of wild populations of Rubia cordifolia L. in Shaanxi province. A total of 182 bands were produced by 14 primers, among which 163 bands were polymorphic bands, and the percentage of polymorphic bands was 89.56%. The average value of Nei's genetic diversity index (H) was 0.293 6, Shannon's information index (I) was 0.444 6, genetic differentiation coefficient (Gst) was 0.555 3, and the gene flow (Nm) was 0.440 8, the wild populations were ranked by genetic diversity:AK > YL > SL > BJ > TC > YA > WN > XY. Mantel Test analysis demonstrated that the significant correlation was found between the genetic distances and geographical distances (r=0.776 4, P < 0.05). There is a significant correlation between geographical and genetic distances. This study provides a theoretical basis for the protection and development of the resources of wild Rubia cordifolia L. germplasms.