Acetaminophen (APAP, also known as paracetamol)-induced liver injury is the leading cause of drug-induced liver injury in the world. Wuzhi Tablet (WZ, an ethanol extract of Schisandra sphenanthera) is widely used in clinical practice to protect liver function. Our previous studies have shown that pretreatment with WZ for 3 days can significantly protect against APAP-induced liver injury; however, the effect of different intervals between APAP and WZ treatment on APAP-induced liver injury remains unclear. In this study, the change in liver injury indexes, APAP metabolites, and the activity of cytochrome P450 (CYP450) enzymes after treatment with WZ and APAP at different intervals were determined. The animal experiment was reviewed and approved by the Animal Ethics Committee of Sun Yat-sen University. The results show that 0 h, 0.5 h, and 2 h pretreatment with WZ significantly protected against APAP-induced liver injury in mice, as evidenced by a significant decrease in biochemical parameters such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and malonaldehyde (MDA). WZ inhibited the metabolic activation of APAP mediated by CYP450 enzymes and reduced the formation of APAP metabolites. This study further demonstrates that pretreatment with WZ at different intervals (0 h, 0.5 h, and 2 h before APAP dosing) exerts a significant hepatoprotective effect against APAP-induced liver injury, and a single-dose of WZ inhibits the activity of CYP450 enzymes related to APAP metabolic activation, thereby protecting against APAP-induced hepatotoxicity.

A LC-MS method was established for the determination of the protein binding rates of oleanolic acid in human plasma and serum albumin. The equilibrium dialysis combined with LC-MS to determine the total concentration in plasma and free drug concentration of oleanolic acid was carried out. The human plasma protein binding rates of oleanolic acid at three concentrations were 79.6%, 81.9% and 63.3%, respectively. The human serum albumin protein binding rates of oleanolic acid at three concentrations were 53.5%, 56.6% and 47.7%, respectively. The method is shown to be simple, accurate, sensitive and specific for the determination of biological samples. The protein binding rates in human plasma and serum albumin were of high strength.
Chromatography, Liquid ; methods ; Dialysis ; Humans ; Mass Spectrometry ; methods ; Oleanolic Acid ; blood ; Protein Binding ; Sensitivity and Specificity ; Serum Albumin ; metabolism

Pregnane X receptor (PXR), a member of nuclear receptor superfamily, plays an important role in xenobiotic and endogenous metabolism, endocrine balance, and cell proliferation, etc. Previous study has shown that pregnenolone 16α-carbonitrile (PCN), a mouse PXR agonist, could induce liver enlargement. And we found that the change in hepatocytes exhibits regional distribution characteristics: hepatocyte enlargement occurs around the central vein (CV) area, while hepatocyte proliferation occurs around the portal vein (PV) area. In this study, the dynamic changes of hepatocytes during PXR-induced liver enlargement were determined. Serum and liver samples from male C57BL/6 mice were collected for biochemical and pathological analysis after PCN treatment for 1, 2, 3, 5 days, respectively. The animal experiment was approved by the Animal Ethics Committee of Sun Yat-Sen University. The results showed that with the increase in the PCN treatment days, the feature of this regional change of hepatocyte around the CV and PV areas became more and more obvious. At the same time, the factors related to hepatocyte enlargement, such as the expression of PXR downstream genes and the hepatic content of triglyceride (TG), has gradually increased. The upregulation of proliferation-related proteins and downregulation of cyclin-dependent kinases inhibitor proteins were observed in the early stage of PCN treatment, suggesting that hepatocyte proliferation occurs earlier than hepatocyte enlargement during PXR-induced liver enlargement. This study reveals the dynamic change of hepatocytes during PXR-induced liver enlargement and provides a new insight in liver enlargement promoted via PXR activation.

The inhibition activity of 36 flavonoids against CYP1A2 was determined by our previously developed in vitro method. The Comparative Molecular Similarity Indexes Analysis (CoMSJA) approach was used to probe the quantitative relationships between the flavonoids' molecular structural descriptors and their inhibitory activities. A reliable CoMSIA model with the combined electrostatic and hydrophobic fields was derived with the regression coefficient R2 of 0.948 and the cross-validation regression coefficient q2 of 0.630, separately, which is capable of elucidating the quantitative relationship between the 3D structural descriptors of the flavones and their bioactivities. Comparing with flavone, the larger pi-pi conjugated system of alpha-naphthoflavone significantly improved the biologically inhibitory ability. Based on the core structure of the latter, either electropositive substituents or hydrophobic groups at the 6, 3', and 4' ring positions or electronegative counterparts at the 5 ring position, can enhance the inhibitory potency against CYP1 A2 according to the CoMSIA contour maps.
Cytochrome P-450 CYP1A2 ; metabolism ; Cytochrome P-450 CYP1A2 Inhibitors ; Flavonoids ; chemistry ; pharmacology ; Humans ; Microsomes, Liver ; metabolism ; Models, Molecular ; Molecular Structure ; Quantitative Structure-Activity Relationship

Nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are originally characterized as transcription factors regulating many target genes. Recent works have revealed that these nuclear receptors play critical roles in regulating genes that encode drug metabolism enzymes and modulating hepatic energy metabolism, such as down-regulating gluconeogenesis, fatty acid oxidation, and ketogenesis, as well as up-regulating lipogenesis. Studies on PXR and CAR have important implication on drug-drug interaction (DDI) and potential disease treatment targets.
Animals ; Drug Interactions ; Energy Metabolism ; Glucose ; metabolism ; Glucose-6-Phosphate ; metabolism ; Humans ; Inflammation ; metabolism ; Lipid Metabolism ; Liver ; metabolism ; NF-kappa B ; metabolism ; Receptors, Cytoplasmic and Nuclear ; physiology ; Receptors, Steroid ; physiology

Drug metabolism will change significantly during inflammation, including the reduction of expression and activity of many drug metabolizing enzymes and transporters. Body would release a series of inflammatory cytokines which can regulate drug metabolizing enzymes. Recent studies have revealed that drug transporters are also regulated by the cytokines with obvious species difference. Mechanism studies show that several transcription factors play important roles during the signal pathways of regulation. This review focuses on the progress in the regulation of drug transporters during inflammation.
ATP Binding Cassette Subfamily B Member 11 ; ATP Binding Cassette Transporter, Sub-Family B ; metabolism ; ATP Binding Cassette Transporter, Sub-Family G, Member 2 ; ATP-Binding Cassette Transporters ; metabolism ; Animals ; Biological Transport ; Humans ; Inflammation ; metabolism ; Membrane Transport Proteins ; metabolism ; Multidrug Resistance-Associated Proteins ; metabolism ; Neoplasm Proteins ; metabolism ; Organic Anion Transporters ; metabolism ; Organic Cation Transport Proteins ; metabolism ; Signal Transduction

Novel solid lipid nanoparticle (SLN) system is prepared with Compritol ATO 888 and tricaprylic glyceride. DSC, XRD, SAXS and NMR are employed to study the novel carrier property and microstructure. When the peak melting point decreased from 70.8 degrees C to 61.4 degrees C, the enthalpy sharply decreased. It could be concluded that the regular crystal lattices in the novel carriers are broken out for the oil joined in them. Melting behavior is occurred at -17.7 degrees C while novel SLN is composed of oil and solid lipid mixture from the DSC measurement. Most alpha phase and least beta' phase are in the nano carrier system whether drug loading or not from the XRD investigation. There is only 0.1 nm change of long space among the novel SLN made of mixture and the lipid matrix and traditional SLN; therefore, it is impossible of the oil molecular insert into the solid glyceride structure. Since the different melting behavior (DSC measurements) and molecular move state (NMR investigations), two lipid matrix are still in two state of liquid and solid lipid in the novel SLN carrier. Presume the microstructure of the novel SLN prepared by our experiment would be that liquid oil has formed superfine nano accommodation encapsulated with solid lipid, but the whole particle is still in nano size range.
Calorimetry, Differential Scanning ; Caprylates ; chemistry ; Diterpenes ; administration & dosage ; chemistry ; Drug Carriers ; chemistry ; Drug Delivery Systems ; Epoxy Compounds ; administration & dosage ; chemistry ; Fatty Acids ; chemistry ; Magnetic Resonance Spectroscopy ; Nanoparticles ; Particle Size ; Phenanthrenes ; administration & dosage ; chemistry ; Triglycerides ; chemistry ; X-Ray Diffraction

OBJECTIVETo investigate the impact of dissected lymph node number on the prognosis of patients with advanced cancer of cardia and stomach fundus.

METHODSClinical data of 236 patients with advanced cancer of cardia and stomach fundus undergone D(2) radical resection were reviewed retrospectively. Five-year survival rate and post-operative complication rate were followed up and their relationships with dissected lymph node number were analyzed respectively.

RESULTSThe 5-year survival rate of the entire cohort was 37.5%. Among those patients with the same stage, the more lymph nodes (LNs) resected, the better survival outcomes achieved(Log-rank trend test P=0.0013). A cut point analysis yielded the ability to detect the significant survival differences. The best long-term survival outcomes were observed with LN counts of more than 20 for stage II(P=0.0136), more than 25 for stage III(P<0.0001), more than 30 for stage IV(P=0.0002) or more than 15 for the entire cohort (P=0.0024), with greatest comparative discrepancies. The post-operative complication rate was 15.7% and was not significantly correlated with dissected lymph node number(P=0.101).

CONCLUSIONSThe prognosis of patients with advanced cancer of cardia and stomach fundus is associated with the number of resected LNs when D(2) lymphadenectomy is carried out. Suitable increment of dissected lymph node number would not increase the post-operative complication rate.

Adult ; Aged ; Cardia ; pathology ; Female ; Gastric Fundus ; pathology ; Humans ; Lymph Node Excision ; Lymph Nodes ; surgery ; Male ; Middle Aged ; Neoplasm Staging ; Prognosis ; Retrospective Studies ; Stomach Neoplasms ; diagnosis ; pathology ; surgery

UPLC-MS-MS system was used for the identification of arbidol metabolites in the rat feces, urine and plasma samples. The system was so powerful a way with high ability of separation and analysis, based on both chromatography and mass properties. The isotope of Br was also a good indicator for metabolites finding. There were altogether 9 metabolites detected and identified, including 2 phase I biotransformation products and 7 phase II ones. It is concluded that arbidol mainly undergo metabolic reactions such as N-demethylation, S-oxidation, glucuronidation and sulfation in rats.
Animals ; Biotransformation ; Chromatography, High Pressure Liquid ; Feces ; chemistry ; Female ; Indoles ; blood ; metabolism ; pharmacokinetics ; urine ; Male ; Rats ; Rats, Wistar ; Tandem Mass Spectrometry

AIMTo explore the effect of the ginkgo bioba extract on the expression of heme oxygenase-1 (HO-1) in bronchial asthma.

METHODS30 guinea pigs were randomly divided into 3 groups (n = 10): (1) Normal control group; (2) Asthmatic group; (3) Therapeutic group. Blood carbon monoxide Hb (COHb) percent value, Airway resistance and eosinophilic inflammation of airway wall were observed, the expression of HO-1 in lung tissue were observed by immunohistochemical staining.

RESULTSThe expression of HO-1 was mainly located in airway epithelium in these 3 groups, the optical densities were 0.170 +/- 0.020, 0.707 +/- 0.058, 0.397 +/- 0.034, respectively. The asthmatic group showed higher optical densities than that of the normal control group (P < 0.01), and the therapeutic group showed lower optical density than asthmatic group (P < 0.01).

CONCLUSIONThe expression of HO-1 is inhibited significantly by the treatment of the ginkgo bioba extract, which may be one of the mechanism for treating asthma by ginkgo bioba extract.

Animals ; Asthma ; drug therapy ; metabolism ; Ginkgo biloba ; Guinea Pigs ; Heme Oxygenase-1 ; metabolism ; Phytotherapy ; Plant Extracts ; pharmacology