Farnesyltransferase (FTase) was selected as a target for virtual screening of inhibitors using the Glide v4.0 program in the Schrödinger software package. We discovered 13 novel structures as farnesyltransferase inhibitors (FTIs) with moderate potency. By analyzing the binding modes of representative compounds 8 (IC₅₀=2.29 μmol·L^-1) and 18 (IC₅₀=0.41 μmol·L^-1) with farnesyltransferase, it was found that compounds 8 and 18 didn't coordinate with Zn²⁺, indicating that the coordination between FTIs with Zn²⁺ is not essential for the bioactivity of the inhibitors. The structure-activity relationship was summarized by analyzing the predicted binding modes of representative compounds. It was found that the scaffolds of the discovered FTIs had room for structural optimization, which lay foundation for obtaining highly active and selective FTIs.

The purpose of this research is to study the anti-atherosclerotic effects and mechanisms of berberine (BBR) in high fat diet (HFD) fed ApoE^-/- mice, and then to lay a solid foundation of the clinical studies of BBR treatment. The hyperlipidemic ApoE^-/- mice model was established by feeding HFD for 12 weeks. Mice were randomly divided into control group (chow diet), model group, BBR group (BBR-L:50 mg·kg^-1, BBR-H:150 mg·kg^-1) and atorvastatin (5 mg·kg^-1) group. Mice were intragastric administration with BBR in 0.5% sodium salt of caboxy methyl cellulose. After 12 weeks, enface aortas were stained with oil red O, and the lesions area were analyzed by Image J software. The inflammatory factor levels were detected by suspension microarray kits. Liver total cholesterol (TC), triglyceride (TG) and free fatty acids (FFA) were determined by commercial kits. Western blot was performed to examine the inflammatory pathway related and cholesterol and lipid transport related proteins' expression. All animal experiments were performed in accordance with the Regulation on the Administration of Laboratory Animals of Institute of Medicinal Biotechnology. After 12 weeks treatment, compared with model group, BBR treatment significantly reduced the lesions area of en face aortas and obviously inhibited serum proinflammatory factors such as IL-1β and IL-6 compared with model group. In addition, BBR treatment obviously reduced liver TC, TG and FFA levels compared with model group. Furthermore, mechanic study showed that BBR significantly inhibited MAPKs and NF-κB pathways, and increased cholesterol and lipid regulated proteins expression such as p-AMPK, LDLR, ABCA1 and SR-BI. In conclusion, BBR can obviously reduce enface aortas lesions in ApoE^-/- mice, which is related to inhibit inflammation and liver cholesterol and lipid accumulation.

Liver fibrosis is a tissue repair compensatory response to liver injury caused by various chronic factors, ultimately leading to liver cirrhosis, liver failure and even hepatocellular carcinoma. Abnormal activation of hepatic stellate cells is the cellular basis of liver fibrosis development. Pepstatin Pr, the derivative of pepstatin A, was isolated from Streptomyces sp. CPCC 202950. Our purpose was to investigate the anti-fibrotic activity of pepstatin Pr and explore its molecular mechanism. Hepatic stellate cell LX-2 was stimulated by TGFβ1 and sub-sequently treated with pepstatin Pr. Its cytotoxicity was detected by sulforhodamine B (SRB) assay. The expression of COL1A1, α-SMA and cathepsin D, signaling proteins TGFβ, Smad and YAP/TAZ were detected by Western blot or real-time PCR. The results showed that pepstatin Pr was not cytotoxic to LX-2 cells. And pepstatin Pr significantly reduced the mRNA and protein expression of COL1A1 and α-SMA, which are important liver fibrosis markers. Pepstatin Pr also repressed the protein expression level of cathepsin D, TGFβ1, YAP/TAZ, the phospholation level of Smad2, and YAP nuclear translocation. In conclusion, pepstatin Pr exhibits anti-fibrotic effects in TGFβ1-stimulaed LX-2 cells by mediating YAP-TGFβ-Smad pathway.

BCS Ⅱ drugs are characterized by low solubility and high permeability. Improving their solubility is considered an important approach to improve its oral absorption. Recent strategies to increase the solubility of poorly-soluble drugs may unexpectedly result in greatly depressed permeability, ultimately leading to failure in improving oral absorption. Based on the mathematics of membrane permeability coefficient of a drug, the membrane/aqueous partition coefficient is dependent on the drug's solubility in the gastrointestinal milieu, suggesting a unique interplay between the solubility and permeability of the drug, and treating the one irrespectively of the other may be insufficient. When we focus on the increase of drug solubility and overlook the efficacy of drug permeability, the positive effect of increased solubility to drug oral absorption might be traded off by depressed permeability. To provide rational formulary designs, by optimizing excipients and evaluation, this review summarizes solubility-permeability interplay for different types of solubilizing techniques, such as cyclodextrin, surfactants-based vehicle, cosolvent, amorphous solid dispersions, other infectors such as P-gp transporters and new techniques for simultaneous evaluation of drug solubility and permeability.

The aim of this study is to investigate the effect of nicotinamide (NIC) on the solubility/dissolution of a poorly soluble drug ibuprofen (IBU), and to explore the mechanism of the formed soluble complex by complexation model, fluorescence quenching and Raman spectroscope. The results showed that NIC could significantly improve the solubility of IBU, and exhibited an A_p type complexation profile. The calculated complexation constants of K_1:1 and K_1:2 were 0.24 and 4.00, respectively. In the solution, the fluorescent intensity of IBU gradually decreased with the increase of NIC, exhibiting the typical fluorescence-quenching phenomenon. The Raman spectrum showed stretching vibrations, bending vibrations, and rocking vibrations ascribed to benzene ring of IBU and pyridine ring of NIC disappeared or significantly shifted, suggested that the soluble complex was formed by dipole-dipole interaction force between the benzene group on IBU and pyridine group on NIC, resulting in the aqueous solubility enhancement of IBU. In comparison to IBU alone, the physical mixture of IBU and NIC showed significantly higher dissolution rate (1.6-fold) and extent.

To modernize traditional Chinese medicine, its pharmacodynamic substances should be elucidated firstly. Modern chromatographic technologies play an important role in the clarification of the pharmacodynamic substances of Chinese medicine. In this paper, the advancement and application of current chromatographic techniques in the pharmacodynamic substances of Chinese medicines were reviewed from the aspects of detection, preparation and screening methods.

This study was designed to prepare a novel lipid bilayer coated hollow mesoporous silica nanocarrier for co-delivery of gene drugs and chemotherapeutic drugs to enhance the inhibitory activity of antitumor drugs in hepatoma cells. Hollow mesoporous silica was synthesized by modified StÖber method. Lipid-fusion principle was used to prepare lipid-hollow co-loaded doxorubicin (DOX) and miR-375 (LHMSN-DOX/miR-375). Meanwhile, the morphology, particle size, surface potential, drug loading and release were characterized in vitro. The inhibition of cell proliferation, cell migration and invasion was then evaluated. The results indicated that the core-shell structure of LHMSN-DOX/miR-375 was clear with an intact outer lipid membrane and an ordered internal HMSN mesoporous structure. The drug release amount was pH responsive while the drug was rapidly released under simulated intracellular acidic conditions relative to normal physiological environment. Compared with free DOX, LHMSN-DOX/miR-375 can deliver DOX and miR-375 to liver cancer cells and inhibit the proliferation, migration and invasion of cells more effectively.

Allium chinense belongs to the genus Alliums of the lily family. It can be used both as medicine and food. To date, the phylogenetic relationship of Allium species have not be resolved completely. Furthermore, there has been a lack of DNA barcode to distinguish closely related species. In this study, the complete chloroplast genome of A. chinense was obtained using next generation DNA sequencing and bioinformatic analysis, and compared with that from other Allium species. The genome is a circular molecule of 152 525 bp with a typical quadripartite structure. Genome annotation identified a total of 116 genes, including 81 protein-coding genes, 31 tRNA genes, and 4 rRNA genes. Analyses of sequences from six Allium species showed that the most diverse regions are found in the protein coding regions such as ndhA and ycf1 genes, and in the intergenic regions, such as ps16-trnQ, trnT-trnF, ndhF-rpl32, rpl32-trnL and rpl16-rps3. A phylogenetic tree was constructed using 58 protein coding sequences from 53 species. All branches showed strong support with bootstrap scores reaching 66%-100%, except those for the Lilium and Paris. Our results suggest that the completed chloroplast genome could solve the classification problems of these species. Using EcoPrimer software, we identified seven markers from the chloroplast genomes, which can be used to differentiate congeneric species. In summary, we have sequenced the complete chloroplast genome of A. chinense, carried out phylogenetic analysis and identified a series of genus specific DNA barcode sequences. The results have laid the foundation for the systematical determination of the phylogenetic relationship of Allium species and the differentiation of species using the genus specific primers.

The aim of this study was to investigate the effect of Jujubae Fructus (JF) on the gastrointestinal toxicity and diuretic effect of Crotonis Semen Pulveratum (CT). Forty-eight mice were randomly divided into the control group, low dose of CT group (0.039 g·kg^-1·d^-1, CTL), high dose of CT group (0.078 g·kg^-1·d^-1, CTH), JF group (9.75 g·kg^-1·d^-1), low dose of CT combined with JF group (CT 0.039 g·kg^-1·d^-1 and JF 9.75 g·kg^-1·d^-1, JFCTL), high dose of CT combined with JF group (CT 0.078 g·kg^-1·d^-1 and JF 9.75 g·kg^-1·d^-1, JFCTH). On the 9^th day of oral administration, the urine output of all mice was measured. After oral administration for ten days, fresh fecal samples were collected, and the 16S rDNA sequencing method was used to study the changes of intestinal bacteria when CT used alone and combined with JF. All experimental protocols were approved by the Animal Ethics Committee of Nanjing University of Chinese Medicine. The results showed that JF slowed down the rapid diuretic effect of CT, and significantly increased serum interleukin-2 (IL-2), interleukin-6 (IL-6), gastrin (GAS), somatostatin (SS). JF also reduced small intestine injury and improved the disorder of intestinal flora caused by CT. Low dose CT combined with JF significantly decreased the relative abundance of Sphingomonas and Oscillospira. The level of Bilophila was decreased after the combined application of high dose CT and JF. The results suggest that JF exhibited a tendency to reduce the toxicity of CT in the aspects of serum immune index, intestinal movement, intestinal damage, and intestinal microflora structure. In addition, the JF could also slow down the rapid diuretic effect of CT, behaving a tendency to reduce the clinical effect of CT.

The solubility of nebivolol hydrochloride was determined in acidic aqueous media in the absence and presence of different concentration of NaCl, NaBr, or NaI at 37℃ in order to facilitate proper selection of dissolution media that have adequate discriminating power for enhancing the likelihood of a generic drug product to successfully pass in-vivo bioequivalence test. In the range of pH 5.0 to pH 1.0, the solubility of nebivolol hydrochloride decreased with the decrease in the pH of aqueous solution, and the solubility of nebivolol hydrochloride further decreased with the increase in the concentration of added sodium chloride. The solubility decrease of a few weakly basic drug molecules in acidic media and in higher concentration of added chloride was published previously by other researchers, and the observed decrease in the solubility in the presence of higher chloride concentration was interpreted in terms of common-ion effect. However, the results in this paper showed that the solubility of nebivolol hydrochloride also decreased when sodium chloride was replaced with sodium bromide or iodide. The approach described in this paper (i.e. substituting sodium chloride with sodium bromide or iodide) provides an effective method to verify whether common-ion effect is the true (or at least the sole) driving force behind the observed decrease in the solubility of nebivolol hydrochloride in the presence of sodium chloride. The solubility decrease reported in this paper can be interpreted in terms of salting-out effect of sodium chloride, bromide, and iodide. For hydrochloride salt of a weakly basic drug molecule like nebivolol hydrochloride, its solubility in an acidic dissolution medium can be purposely decreased to the lower end of sink condition by adding sodium chloride to make the resulting medium more discriminating. As shown in this paper, a medium at pH 1.2 with added sodium chloride is discriminating and this medium is shown to be bio-relevant to the in-vivo data collected under fasting condition (in-vivo study protocol was approved by Institutional Review Board).