Latest ArticlesA method for determining dipropofol in the plasma of Beagle dogs was established by HPLC-MS/MS. We also studied the pharmacokinetic characteristics of two different forms of crystal tablets of dipropofol in Beagle dogs. All animal experiments were approved by the Animal Experimental Management, Welfare and Ethics Committee of Pharmacology Evaluation Research Center, Shanghai Institute of Pharmaceutical Industry. The results indicate that the maximum plasma concentration (Cmax) of dipropofol was 69.02 ±20.16 μg·L-1 after 20 mg·kg-1 crystal form Ⅰ tablet taken orally, and the AUC0-t was 160.49 ±55.26 μg·L-1·h. After 20 mg·kg-1 crystal form Ⅱ tablet taken, the Cmax of dipropofol was 92.58 ±60.26 μg·L-1, and the AUC0-t was 243.59 ±148.36 μg·L-1·h. The AUC0-t and Cmax of crystal form Ⅱ were significantly different from that of crystal form Ⅰ (P < 0.05). Crystal form Ⅱ was the dominant crystal form. The results suggest that we should control crystal form during the development of dipropofol oral tablets.
To provide a basis for the establishment of the commodity grade of Astragali Radix (AR), we compared the chemical components and the anti-fatigue effect of different grades of AR. The components of primary metabolites were analyzed by 1H NMR and the contents of five flavonoids were determined by HPLC-UV with different grades of AR. Fatigue efficacy of different grades of AR was compared. All the procedures were approved by the Laboratory Animal Ethics Committee of the Shanxi University. The results showed that the content of water soluble extracts (WSE) of the Grade Ⅱ AR was the lowest, and 21 compounds were identified through 1H NMR spectrum. There are 3 components showing a higher content in the Grade-top AR, and 7 components were higher in the Grade-Ⅳ, and 7 other components were higher in the Grade-Ⅱ AR. Total flavonoid content was the highest in Grade-Ⅱ but it was the lowest in the Grade-Ⅳ. Pharmacodynamic results showed that AR could significantly enhance the exhaustion time of rats and improve the biochemical indexes of serum and gastrocnemius muscle, and the best anti-fatigue effect was observed with Grade -Ⅱ AR. Therefore, chemical composition and efficacy index were used to evaluate the quality of different grades of AR, and the quality evaluation approach was established based on chemical and pharmacological effects to provide a scientific basis for the development of AR. The study may provide useful information for construction of the quality grade standard of AR.
This study aimed to evaluate the effects of Jiawei Foshou San capsule (JWFSSC) on CYP1A2, CYP2C6, CYP2D2, CYP2E1 and CYP3A1/2 enzyme activities in rat liver microsomes in vitro and in vivo, and to provide pharmacokinetic data for its combined use with other medicines. After incubating liver microsomes with a cocktail of probe drugs, the metabolites were quantitated with LC-MS/MS to assess the CYP enzyme activity. The hepatic pathological changes were evaluated by histology after hematoxylin and eosin (HE) staining. With the dose range up to 3 200 mg·L-1, the IC50 of JWFSSC for CYP2D2, CYP2E1 and CYP3A1/2 in vitro was 229.3 mg·L-1, 361.9 mg·L-1 and 274.6 mg·L-1 respectively. Compared with the vehicle control group, the enzyme activities of CYP1A2, CYP2C6 and CYP3A1/2 showed a significant increase in animals given JWFSSC 180 mg·kg-1·d-1 (P < 0.01). Based on histology, several pathological changes were observed in JWFSSC groups:there was less inflammatory infiltration compared to the tetrahydropalmatine (THP) group. These results of inhibition in vitro and induction in vivo suggest a strengthened efficacy and a prolonged effective time of drugs metabolized by CYP2D2 and CYP2E1 enzymes when combined with JWFSSC in use. The dosage of parent drugs should be appropriately reduced when used in combination with JWFSSC. However, if a drug is metabolized by CYP1A2 and CYP2C6 when used in combination with JWFSSC, the effect of the drug is likely reduced and the dosage should be increased appropriately. In addition, the combination of ferulic acid (FA), ligustrazine (LZ) and THP can significantly reduce the toxicity of THP in rat livers. In this study, the program of animal testing had been approved by Committee on the management and usage of experimental animal in the College of Pharmaceutical Sciences, Southwest University.
CAT3 is a promising anti-brain tumor agent that has significant anti-tumor activity on Daoy or U87MG orthotopic xenograft in nude mice. This study was carried out to investigate the metabolic profiles of CAT3 in mouse/dog/human blood and microsome as well as in humanized recombinant enzymes. All animal care and experimental procedures were reviewed and approved by the Animal Ethics Committee of Chinese Academy of Medical Sciences. Our findings showed that CAT3 could be hydrolyzed to active metabolite PF403 by carboxylesterase, butyrylcholinesterase and serine hydrolase in mouse/dog/human blood. PF403 could be further metabolized to M1 oxidative dehydration product, M2 double oxidation dehydration product, M3 methylation oxidative dehydration product, M4 oxidation product and M5 demethylation product, which were mainly catalyzed by CYP1A2, 1A1, 2C9 and 3A4, and slightly by CYP2B6, 2C8, 2C19 and 2D6. Besides oxidative metabolism, PF403 also was transformed into glucuronylation metabolites GLU-PF403 by Phase Ⅱ enzymes UGT1A1, 1A3 and 1A9. Taken together, the metabolism of CAT3 was a multiple enzyme catalytic reaction. These results could provide valuable information for potential enzyme-mediated DDI in clinic studies.
In this paper, a new type of preparation for treatment of initial dry eye disease, thermosensitive in situ gel, was prepared using levocarnitine as a model drug. Poloxamer 407 and poloxamer 188 were used as the gel matrix, and sodium hyaluronate and sodium carboxymethylcellulose were used as bioadhesive materials. Gelation temperature was determined by a rotor method and the prescription was optimized by central composite design-response surface methodology. The pH value, viscosity value and gelation temperature of the optimal prescription were measured. The release of the drug in vitro was examined by dialysis membrane permeation, and retention time of the thermosensitive in situ gel preparation on the rabbit's ocular surface was observed by a slit lamp microscope. The results showed that the dosage of the poloxamer 407 and poloxamer 188 were 20.81% and 3.46%, respectively, and sodium hyaluronate was 0.02%, sodium carboxymethyl cellulose was 0.10% of the optimal formulation of levocarnitine thermosensitive in situ gel. The pH value was 6.90 ±0.06 at room temperature and the viscosity value started to rise sharply at 27℃ of the optimal formulation. The gelation temperature of the optimal preparation before and after dilution by simulated tear fluid were (26.37 ±0.06)℃ and (33.57 ±0.21)℃, respectively. In the first 240 min, in vitro release rate per unit area of levocarnitine thermosensitive in situ gel was lower than that of solution (P < 0.05), and after 600 min, the cumulative release rate of levocarnitine thermosensitive in situ gel could reach more than 80%. The retention time of the thermosensitive in situ gel preparation on rabbit's ocular surface reached about 25 min, at least 5 times as much as that of the solution. The animal experiment was conducted following the National Institutes of Health Guidelines for the use of experimental animals, and approved by the Ethics Committee of the Experimental Animal Center of Beijing University of Chinese Medicine. The levocarnitine thermosensitive in situ gel showed good characteristics and sustained release property and significantly improved the retention time of the drug on the rabbit's ocular surface.
This study aimed to construct an intelligent fluorescent nanocarrier for tumor cell tracing. Doxorubicin (DOX) was used as a model drug, and the gene targeting siBcl-2 was loaded to achieve synergistic inhibition of tumor cells. Mesoporous silicon nanoparticles (MSN) were prepared by a sol-gel method, and acetaldehyde cystine (AC) and polyethyleneimine (PEI) were covalently modified. The prepared nanocarrier MSN-AC-PEI was uniformly dispersed, with a particle size of 235.53 nm and a potential of 14.63 mV. The carrier material MSN-AC-PEI could load siRNA with the mass ratio of 60:1 (Wvectors:WsiRNA) and protect siRNA from RNase I degradation. To simulate the microenvironment of tumor, DOX release in phosphate buffer (pH 5) including 10 mmol·L-1 glutathione (GSH) was investigated. The cumulative release rate of DOX at 120 h is 35 times that of the normal physiological environment, which lays the foundation for the intelligent release of DOX in tumor cells. The results of cell experiments showed that the carrier material MSN-AC-PEI had significant green fluorescence, and the traceability can be maintained for 24 h after taken up by MCF-7 cells. After 24 hours of administration of the nano drug delivery system MSN-AC-PEI@DOX/siBcl-2, the inhibition rate of tumor cell proliferation reached 40.91%, and the late apoptosis rate was 60.84%. The Western blot results showed that compared with free DOX and siBcl-2, the nano-delivery system MSN-AC-PEI@DOX/siBcl-2 can significantly reduce the expression of anti-apoptotic protein Bcl-2, thereby enhancing its anti-tumor ability.
In this study, 13 xyloglucan endotransglycosylases/hydrolases (XTHs) and 8 expansin (EXPs) were screened from safflower floret transcriptome database. Through correlation analysis between the safflower gene expression profile chip and the corolla development, only 4 XTHs (CtXTH1-4) and 1 EXP (CtEXP1) have positive relevance with corolla elongation (r ≥ 0.60) and were therefore validated by qRT-PCR. The full length of these genes were cloned by RACE. According to the bioinformatic analysis, CtXTH1 correlated with the development of the floret, and the expression pattern analysis indicated that CtXTH1 had accumulated in the floret. The recombinant vector (pMT39-CtXTH1) was constructed for gene transformation. Overexpression of CtXTH1 significantly increased the corolla length (about 5.34% to 10.25%) and corolla weight (about 30.00% to 36.02%) in transgenic safflower. The overexpression lines also showed an increasing tendency in the weight of seeds, average number of corollas per cone and average number of seeds in each cone. Meanwhile, overexpression of CtXTH1 had no significant effect on flavonoids. According to the corolla microstructure, the OVX-line tubular part of floret exhibited a looser and irregular character. These data suggested that CtXTH1 can potentially increase relaxation of the tissues and boost corolla elongation. Our study provides a valuable clue for plant breeding in the future.
Among various technologies used in drug design and discovery, deep learning is still in its infancy. Recently, deep learning approaches have been rapidly developed and applied to address various problems in drug discovery, including generation of virtual compound library, prediction of compound activity, metabolism and toxicity, and prediction of organic synthesis routes. Compared with the traditional machine learning methods, the prediction power of deep learning did not show significant improvement. However, proactively learning and automatically feature extraction bring advantages for deep learning approaches. Compared to first principle-based computational chemistry methods, deep learning can not be generalized because it depends on large-scale and highquality annotated data sets. But its molecular representation with single-atom atomic environment vectors could be useful for computational chemists. As an emerging technology, deep learning, especially the unsupervised learning method that does not rely on large datasets with labels, is gradually improving. It is expected that someday deep learning method will become practical for drug discovery.
Akkermansia muciniphila (A. muciniphila) is an intestinal bacterium that was isolated from human feces in 2004. Its specialization in mucin degradation makes it a key organism that maintains the intestinal mucosal barrier function. A. muciniphila, which is the only representative of the Verrucomicrobia that can be cultured, is relatively easy to be detected in metagenomic analysis. For the past few years, A. muciniphila has quickly attracted the attention of researchers and become a medical and biological hotspot due to the close correlation between its intestinal colonization and the development and progression of various metabolic diseases. This review introduces the biological characteristics and colonization environment of A. muciniphila, and reviews its relationship with host health and disease, especially focusing on the metabolic disease and related mechanism, as well as the factors affecting its colonization in the host, expecting to provide evidence and clues for drug development targeting A. muciniphila.
Protein acetylation is a process of adding an acetyl group to a protein lysine residue with the help of acetyltransferase, which is a pivotal protein post-translational modification linking acetyl-CoA metabolism and cell signal transduction. Recently, the development of mass spectrometry has deepened our understanding of lysine acetylation. Lysine acetylation is involved in many processes such as gene transcription, protein degradation, cellular metabolism, and stress response, which affects biological processes by regulating protein interactions, activity, stability and localization. Protein acetylation is widely happened and plays important regulatory roles in a diversity of human diseases such as metabolic diseases, tumors and cardiovascular diseases. Besides, deacetylase inhibitors have displayed a great potential in the treatment of various diseases especially tumors and metabolic associated diseases. In this review, we summarized the advances and application of acetylation, and discussed the remaining problems in this area.
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