Cyclophosphamide (CPA) is one of the most commonly used alkylating agents in the treatment of malignant cancer. CPA is metabolized by cytochrome P450 enzymes into 4-hydroxycyclophosphamide in vivo which can exhibit anti-tumor activity. Metabolic activation of CPA can cause adverse reactions such as myelosuppression, cystitis, and liver injury. The aim of this study was to evaluate the dynamic changes of hepatic injury induced by CPA in mice. Male BALB/c mice were injected CPA (200 mg·kg^-1) intraperitoneally. Both serum and liver samples were collected at 0, 2, 6, 12 and 24 hours after dosing. The animal experiment protocol was approved by the Institutional Animal Care and Use Committee at Sun Yat-sen University. The results showed that hepatotoxicity was observed at 2 hours after CPA dosing, and the most serious liver injury was measured at 12 hours. The level of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and malondialdehyde (MDA) was significantly increased, glutathione (GSH) level was significantly decreased, hepatocyte edema and vacuolar degeneration were widely observed in liver tissue, and began to recover 24 hours after dosing. In addition, due to oxidative stress damage caused by CPA, nuclear factor-erythroid 2-related factor 2 (NRF2) signaling pathway was activated and the mRNA and protein expression of its downstream targets such as quinine oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), glutamate-cysteine ligase catalytic subunit (GCLC) and glutamate cysteine modifier subunit (GCLM) were up-regulated, which alleviated oxidative stress injury. In a summary, this study demonstrate the dynamic change of CPA-induced liver injury and the NRF2-mediated protective mechanisms, providing new insights into the CPA-induced liver injury.

The rat models of focal cerebral ischemic reperfusion and subarachnoid hemorrhage were used to evaluate the therapeutic effects of artificial musk to provide support for its clinical application. All animal experiments were performed following the regulations of the Animal Ethics Committee of Peking Union Medical College. The results showed that oral administration of artificial musk had significant protective effects on acute ischemic and hemorrhagic stroke. In the dose range of 10-200 mg·kg^-1, the mortality, neurobehavioral and cerebral infarction volume of rats in model group indicated a clear dose dependent relationship. The effective dose of artificial musk is 10 mg·kg^-1 in ischemic stroke and 200 mg·kg^-1 in hemorrhagic stroke. These findings suggest that the treatments of artificial musk in ischemic stroke and in hemorrhagic stroke are different, and such differences should be noted for its clinical use.

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 (W_vectors:W_siRNA) 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.

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.

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.

A 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 (C_max) of dipropofol was 69.02 ±20.16 μg·L^-1 after 20 mg·kg^-1 crystal form Ⅰ tablet taken orally, and the AUC_0-t was 160.49 ±55.26 μg·L^-1·h. After 20 mg·kg^-1 crystal form Ⅱ tablet taken, the C_max of dipropofol was 92.58 ±60.26 μg·L^-1, and the AUC_0-t was 243.59 ±148.36 μg·L^-1·h. The AUC_0-t and C_max 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.

Exosomes are membranous vesicles that are actively secreted by cells. They can be isolated from various cell culture media and animal body fluids. Exosomes are mainly composed of lipids, proteins and nucleic acids. They have small molecular structure and high biocompatibility with size of 40-100 nm. In addition, exosomes are natural endogenous nanocarriers that can transport lipids, proteins, DNA and RNA. Studies have shown that exosomes play an important role in long-distance communication between cells, in physiological and pathological processes. This article introduces the composition and physiological functions of exosomes, and summarizes the relevant content of exosomes as drug delivery vehicles. The applications of exosomes in central nervous system diseases, especially brain diseases and tumors are summarized.

This paper summarizes research progresses of Chinese scholars in the field of drug metabolism and pharmacokinetics (DMPK) in 2018. Chinese scholars focused on drug metabolizing enzymes and transporters, and carried out studies on the mechanisms of drug metabolism and transport of active molecules. Topics of research included regulatory mechanisms of drug metabolizing enzymes or transporters, and their implications in drug development and disease etiology or progression. Here, we summarized studies on drug toxicity based on drug metabolism or transport, rational drug use in the clinic, drug metabolism mediated by intestinal flora, metabolism of traditional Chinese medicines, and new technologies or models in DMPK. In recent years, the research focus of drug metabolism in China has transformed from serving for new drug discovery and rational use, to innovation driven and mechanism oriented research. The domestic research topics and technology utilization are gradually aligning with the international conventions.

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.

Phosphoglycerate kinase 1 (PGK1) is a key metabolic enzyme in the glycolysis pathway, which catalyzes the transfer of 1, 3-bisphosphoglycerate (1, 3-BPG) to 3-phosphoglycerate (3-PG) with ATP production. Over-expression of PGK1 has been observed in many types of malignance. Besides as a metabolic enzyme, PGK1 can also act as a protein kinase, which promotes the development and progression of tumors and correlates with chemoradiotherapy resistance and poor survival of cancer patients by regulating tumor cell metabolism. Functions of PGK1 were summarized in this article to provide theoretical basis for PGK1-targeting drug development.