Lung cancer ranks the first in the mortality rate among all cancers, and non-small cell lung carcinoma (NSCLC) accounts for about 80% of the incidence of lung cancer. In recent years, the drugs targeting specific molecules have been developed rapidly. The epidermal growth factor receptor-tyrosine kinase inhibitors (EGFRTKIs) have achieved good results in the treatment of patients with NSCLC. Currently, there are three generations of EGFR-TKIs, and the treatment outcome of these drugs surpasses traditional chemotherapies. However, the problems of acquired resistance remains in the course of treatment. In this review, research progress of the mechanisms of acquired resistance is divided into two parts:EGFR-dependent pathway and EGFR-independent pathway. The EGFR-dependent pathway mainly includes EGFR gene mutations, whereas the EGFR-independent pathways include HER2 amplification, BIM deletion, activation of HGF/c-Met pathway, activation of IGF1R, RAS mutation, PTEN deletion, epithelial-mesenchymal transition, PUMA loss, and high levels of expression of VEGF or IL-6. These interconnected mechanisms are linked with acquired resistance to EGFR-TKIs in NSCLC.

Antiretroviral therapy has been used for treating AIDS with 31 single-target anti-HIV drugs currently on market. Searching for safe and effective of novel anti-HIV drugs remains a challenge worldwide. Multi-targets single-structure compounds referred to as designed multiple ligands (DMLs) have become a hot topic of producing anti-HIV drugs recently due to reduction in the likelihood of drug resistance, simplified dosing and improved patient adherence. Integrase (IN) and ribonuclease H (RNase H) are two indispensable enzymes in HIV republication, therefore are two important targets for developing anti-HIV drugs. Recently, diverse dual inhibitors of HIV IN and RNase H (IN/RNase H) have been developed via rational drug design and screening. This review summarizes the advances in chemically synthesized dual inhibitors of HIV IN/RNase H to provide the information for developing multi-targets anti-HIV drugs.

6-Bromo-3-n-butylphthalide was obtained by nitration, reduction and diazotization from carboxybenzaldehyde. Twenty hybrids from substituted styrene and 6-bromo-3-n-butylphthalide were synthesized and the structure was confirmed by ¹H NMR, ¹³C NMR and ESI-MS. All compounds were evaluated for neuroprotective activity against OGD/R-induced neurotoxicity in rat cortical neurons by MTT assay. The mechanism of neuroprotection was investigated by Western blot analyses. The results indicated that most of these compounds had a potent neuroprotective activity (All animal experiments were approved by the Experimental Animal Ethics Committee of Anhui University of Chinese Medicine), especially 10h and 10i showed significant effects, which may play a neuroprotective role by activating the PI3K/Akt signaling pathway.

This research is aimed to investigate the effect of ampelopsin on apoptosis and migration of human hepatoma SMMC-7721 cells and explore the molecular mechanism. SMMC-7721 cells were pretreated with different doses of ampelopsin and cells proliferation was detected by CCK8 kit. Cell morphology was observed under an inverted microscope. Nuclear morphology was detected by DAPI staining. Apoptotic rate was detected by Annexin V-FITC/PI flow cytometry. Migration and invasion were detected by Transwell and scratch healing test. Western blotting was used to detect cleavage of poly ADP-ribose polymerase (PARP), expression of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), E-cadherin, and N-cadherin, and phosphorylation of ERK, P38 and JNK in MAPKs pathway. Our results showed that ampelopsin significantly inhibited proliferation and induced apoptosis of SMMC-7721 cells, with half inhibition dose (IC₅₀) for 24 h was 38.98 μg·mL^-1. With 50 μg·mL^-1 ampelopsin treatment, typical apoptotic morphological changes occurred, such as cell detachment, shrinkage and nuclear condensation. Apoptotic rate increased from 15% to 55.1%, with PARP cleavage significantly increased. In addition, treatment of ampelopsin reduced scratch healing of cells and transmembrane cells number. The expression levels of MMP-2 and MMP-9 were decreased. Further analysis of EMT-related proteins showed that after ampelopsin treatment, E-cadherin was up-regulated and N-cadherin was down-regulated. During ampelopsin treatment, ERK reached its peak of activation after 1 h, while the maximum activation time of JNK was 12 h. Meanwhile, P38 was activated within 4 h, with the highest point at 2 h. But after 4 h, ampelopsin inhibited phosphorylation of P38. These results indicated that ampelopsin induced apoptosis and reduced migration through activating MAPKs pathway and reversing EMT process in SMMC-7721 cells. This work provides a mechanistic basis for utilizing ampelopsin for anti-hepatocarcinoma treatment.

Nine compounds were isolated from 95% ethanol extract of the roots of Tagates erecta by silica gel column chromatography and Sephadex LH-20 chromatography. Their structures were identified by spectroscopic data as 5-hydroxymethylfurfuryl methyl succinate (1), 5, 7, 3'-trihydroxyl-3, 6, 4'-trimethoxylflavone (2), syringic acid (3), 5, 7, 4'-trihydroxyl-3, 6-trimethoxylflavone (4), patuletin-4'-methoxyl-7-O-β-D-glucopyranoside (5), patulitrin (6), 5, 3'-dihydroxyl-3, 6, 4'-trimethoxylflavone-7-O-β-D-glucopyranoside (7), (2, 2'-biththiophen)-5-ol (8), and 3-hydroxyl-4-methoxyl benzoic acid (9). Among them, compound 1 is a new disubstituted succinate and compound 8 was isolated from a natural resource for the first time. Compounds 2, 4, 5 and 9 were isolated from this genus for the first time. By measuring the biological activity and virulence of different compounds against soybean cyst nematode, it has found that compounds 1-8 exhibited a toxic effect on soybean cyst nematode, and ED₅₀ values indicate that compounds 3 and 7 are the most potent, with ED₅₀ values of 0.008 μg·mL^-1.

This study was designed to investigate the inhibitory effect and mechanism of neferine (Nef) on invasion and metastasis of nasopharyngeal carcinoma cells (NPC). The viability of CNE-1 and 5-8F cells was detected by CCK-8 assay after treatment with different concentrations of Nef. The effects of Nef on cell migration and invasion were detected by the scratch test and Transwell assay. Western blot analysis was used to detect the effects of Nef on levels of epithelial-mesenchymal transition (EMT)-associated proteins and transcription factors. The differentially expressed gene profiles between control group and Nef group were analyzed by microRNA microarray, combined with bioinformation analysis. It was observed that 30 μmol·L^-1 Nef had no significant effect on the viability of CNE-1 and 5-8F cells. Western blot assay showed that the expression level of neurotroponin cadherin (N-cadherin) and vimentin decreased after treatment with Nef, while the expression of epithelial cadherin(E-cadherin) increased. The expression of transcription factors including Twist, Snail, and Slug exhibited no significant difference. Results of the microRNA microarray suggest that 10 microRNAs showed significant differences when compared with the control group. Bioinformatics analysis showed that hsa-let-7c-5p and hsamicroRNA-423-5p targeted the same downstream genes:small integral membrane protein 3 (SMIM3) and nerve growth factor (NGF). Overexpression of hsa-let-7c-5p and hsa-miR-423-5p promoted the invasion and migration ability of 5-8F cells and decreased the expression of SMIM3 and NGF. The results from this study suggest that Nef may inhibit the invasion and metastasis of NPC cells by inhibiting the expression of hsa-let-7c-5p and hsamiR-423-5p followed by the upregulation of SMIM3 and NGF; thus, regulating the expression of EMT-associated proteins. Our data have provided experimental evidence for the inhibition of tumor invasion and metastasis by Nef.

The aim of this study is to solidify the volatile oil (VO) of Bupleuri radix and forsythiae fructus by using mesoporous silica Sylysia 350FCP (Sylysia 350FCP) as carrier, and to investigate the changes of micromeritic properties before and after drug loading. The volatile oil drug-loading powder (VO-DLP) was prepared by blending process. The micromeritic properties were evaluated by angle of repose, particle size, bulk density, true density and porosity. The compressibility and compactibility of the powder were evaluated by plastic strain energy, ejection force, friction energy and tensile strength. The powder was characterized by scanning electron microscopy, powder X-ray diffraction and synchronous thermal analysis. In addition, the thermal stability, mechanical stability and other key properties of VO-DLP were investigated. We found that mesoporous silica as a carrier of solidifying volatile oil has the advantages for large drug load, high thermal stability, and high mechanical stability. In addition, the excellent properties of mesoporous silica as solid lubricant and glidant are not affected after loading VO, and has no effect on the compression process and compactibility of materials. What's more, it can meet the demand of continuous production.

The surface hydrophobicity of nanoparticles plays an important role in drug delivery process. The aim of this study was to verify the feasibility of using self-assembly method to prepare drug-loaded nanoparticles with tunable surface hydrophobicity. Here, Soluplus was selected as the polymeric carrier to prepare panobinostat (PNB) loaded micelles. Three different monoglycerides, glycerly monooleate (GMO), glycerly linoleate (GML) and glycerly linolenate (GMLO), were used to modify the surface of PNB-Soluplus micelles to prepare polymerlipid hybrid nanoparticles (PLHNs). The effect of monoglyceride type and amount on the physico-chemical properties of PNB-loaded PLHNs was investigated, and the surface hydrophobicity of PLHNs was characterized by Rose Bengal (RB) binding method and mucin particle method. The results suggested that compared with the PNB-Soluplus micelles (particle size 77.97±0.78 nm, zeta potential 0.44±0.29 mV, entrapment efficiency 99.45%±1.47%, the RB binding constant (K) value 0.008±0.002, the increased particle size after mixing with mucin particles 7.90±1.41 nm), surface hydrophobicity of the PLHNs increased significantly when modified by GMO, GML, GMLO, with K values of 0.055±0.010, 0.050±0.011 and 0.058±0.008, respectively. The increased particle sizes after mixing with mucin particles were 17.37±4.48 nm, 22.60±2.10 nm and 25.13±3.89 nm, respectively. Among them, the physico-chemical properties of the GMLO modified PNB-loaded PLHNs (particle size 81.60±4.52 nm, zeta potential 0.77±0.03 mV, entrapment efficiency 99.59%±0.20%) kept constant, thus GMLO was selected to further investigate the effect of GMLO mass ratio (1%-3%) to Soluplus on the properties of the nanoparticles. While no statistical significant difference in particle size, zeta potential, entrapment efficiency or in vitro release behavior was found when GMLO ratio increased, the surface lipophilicity of the PLHNs, as characterized by K values and the increased particle sizes after mixing with mucin particles, increased almost linearly with the increase of GMLO amount. In conclusion, we demonstrated that drug-loaded PLHNs based on Soluplus and GMLO can be prepared by self-assembly method, and the surface hydrophobicity was tunable by modifying the mass ratio of GMLO to Soluplus. This approach could be used for related basic science research aiming to elucidate the effect of surface hydrophobicity on in vivo behavior of drug-loaded system.

About 15%-20% of drug-induced liver injury (DILI) will progress to chronic manifestation (CH-DILI), which sometimes advances rapidly to liver cirrhosis (LC-DILI) within 0.5-1 year with deteriorative clinical prognosis. Therefore, it is important to find a non-invasive diagnosis for early detection of liver cirrhosis. In this study, the metabolomic profiles revealed significant differences in the metabolites from the plasma of LC-DILI versus CH-DILI. We found 35 differential metabolites through principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA). Through pathway enrichment analysis, some up-regulated metabolic pathways reflected impaired liver functions such as bile acid, lipid synthesis and decomposition during cirrhosis. Five biomarkers were found to exhibit effective diagnosis value (AUC > 0.6), including phosphatidylcholine, lysoPC (18:1 (9Z)), creatine, taurochenodeoxycholic acid and taurocholic acid. Furthermore, we found that the relative content ratio between phosphatidylcholine and lysoPC (18:1 (9Z)) had a better distinguishing ability (AUC=0.867). The relative content ratio also had the feature to reduce systematic errors of sample processing and instrument detection, therefore having a greater value for clinical application.

The purpose of current study is to investigate the metabolic profile of a triptolide derivative (5R)-5-hydroxytriptolide in vitro. (5R)-5-Hydroxytriptolide was incubated with the hepatocytes of human, monkey, dog, rat or mouse, respectively. Compared with inactivated hepatocytes, four metabolites were identified in hepatocytes from all five species:oxidative ring-opening metabolite (M1), glutathione-conjugating metabolite (M2), and monooxidative combined with glutathione-conjugating metabolites (M3-1 and M3-2), respectively. In human or rat liver microsomes, seven metabolites of (5R)-5-hydroxytriptolide were found, dehydrogenated metabolite (M4) and monooxidative metabolites (M5-1-M5-6), respectively. Reference standards for the metabolites were obtained either through chemical semisynthesis or biotransformation through rat primary hepatocytes. The structures of five metabolites were confirmed, which were 12, 13-epoxy ring-opening metabolite M1, 12-glutathione-conjugating metabolite M2, (16S)-, (2R)- and (19R)-monohydroxylated metabolites M5-1, M5-4, and M5-5, respectively. In vitro activity assay revealed that only (2R)-hydroxylated metabolite exhibited weak immunosuppressive activity with less than one-tenth the activity of its parent drug, and a significant decrease in toxicity was observed. It is suggested that (5R)-5-hydroxytriptolide might undergo metabolic inactivation and detoxification in vivo.