Exp Toxicol Pathol. 2009 Jun 18; Liu TY, Chen Y, Wang ZY, Ji LL, Wang ZTIsoline is a retronecine-type pyrrolizidine alkaloid (PA) isolated from the traditional Chinese medicinal herb Ligularia duciformis. The present investigation was carried out to evaluate isoline-induced oxidative injury in various important mouse organs. Various tissue samples were collected after mice were administrated with 100mg/kg isoline for 36h, and then lipid peroxidation (LPO) level, total antioxidant capacity, glutathione-S-transferase (GST), glutathione peroxidase (GPx) and catalase (CAT) activities were determined to evaluate the oxidative injury. Our results showed that the total antioxidant capacity of liver, brain and lung were all decreased after given isoline, and the LPO level was increased in liver and heart of isoline-treated mice. Further antioxidant-related enzyme activity assays showed that isoline (100mg/kg) decreased GPx activity in liver and heart, increased CAT activity in liver, brain and heart, and decreased the GST activity in lung. Taken together, our results demonstrate that isoline can induce different oxidative injury in various important mouse organs, and of which liver is the most sensitive organ.

Yao Xue Xue Bao. 2009 Apr; 44(4): 355-61Cao YL, Li SX, Chen H, Guo YConsistent non-nucleoside reverse-transcriptase inhibitors (NNRTIs) resistant HIV-1 strains occurred due to the clinical use for more than ten years of efavirenz (EFV), nevirapine (NVP), and delavirdine (DLV). In this study, we established nine cell-based pharmacological models according to most NNRTIs-resistant clinical tested strains, Resistant mutations were introduced into vector, pNL4-3.Luc.R-E-, by overlapping PCR. Then, pseudovirions were produced by co-transfection of VSV-G plasmid and pNL4-3.Luc.R-E- -mut. All nine recombinant VSVG/HIV-mut pseudovirions (VSVG/HIV-wt, VSVG/HIV(-K103N), VSVG/HIV(-Y181C), VSVG/HIV(-L100I,K103N), VSVG/HIV(-Y188L), VSVG/HIV(-K103N,Y181C), VSVG/HIV(-K103N,P225H), VSVG/HIV(-K103N,Y188L), VSVG/HIV(-K103N,G109A) and VSVG/HIV(-K103N,V108I)) had high efficient infectivity. Furthermore, they all showed resistant characteristics to EFV and NVP with IC50 changes consisting with clinical reports, not to nucleoside reverse-transcriptase inhibitors (AZT and d4T). This series safe cell-based model, which could be carried out in BSL-2 laboratory, can be used for evaluating NNRTIs candidates.

Acta Pharmacol Sin. 2009 Jun 22; Li QN, Liu HY, Xin XL, Pan QM, Wang L, Zhang J, Chen Q, Geng MY, Ding JAbstractAim:To elucidate the detailed mechanisms underlying the appreciable effects of JG3, a novel marine-derived oligosaccharide, on cell migration using a Chinese hamster ovary (CHO) cell line stably over-expressing heparanase.Methods:A retrovirus infection system was used to establish a CHO-K1 cell line stably transfected with heparanase. Immunocytochemistry was used to assess cell morphology. Flow cytometry was selected to analyze the activation of beta1-integrin, and Western blotting was used to analyze the downstream effects on the cell adhesion pathway. An affinity precipitation assay was used to determine activation of the small GTPases, Rac1, and RhoA.Results:JG3 abolished heparanase-driven formation of focal adhesions and cell spreading. Although JG3 failed to block the heparanase-triggered activation of beta1-integrin or the phosphorylation of Src, the oligosaccharide caused a significant dephosphorylation of FAK and subsequent inactivation of Erk. Furthermore, JG3 was found to arrest the activation of Rac1.Conclusion:All these findings help form an alternative view to understand the mechanisms underlying the inhibitory effects of JG3 on cell motility.Acta Pharmacologica Sinica advance online publication, 22 June 2009; doi: 10.1038/aps.2009.97.

Nat Med (Tokyo). 2009 Jun 24; Gao XH, Xu XX, Pan R, Li Y, Luo YB, Xia YF, Murata K, Matsuda H, Dai YSepsis remains the leading cause of death in intensive care units. Uncontrolled systemic inflammation and an impaired protein C pathway are two important contributors to sepsis pathophysiology. Based on the beneficial effects of the saponin fraction from Astragalus membranaceus roots (SAM) against inflammation, liver dysfunction, and endothelium injury, we investigated the potential protective roles and underlying mechanisms of SAM on polymicrobial sepsis induced by cecal ligation and puncture (CLP) in mice. SAM, orally administered 1 h before and after CLP, significantly elevated the survival rate of mice. At 96 h after CLP operation, all mice in the model group died, whereas 33.3% of mice in the SAM (400 mg/kg)-treated group survived. SAM attenuated both inflammatory factors and their abilities to induce tissue dysfunction, which was mainly evidenced by decreased infiltration of polymorphonuclear leukocytes, tissue edema, and lung wet-to-dry weight ratio, lowered levels of myeloperoxidase (MPO), nitric oxide (NO), lactate dehydrogenase (LDH), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) in serum, as well as downregulated expressions of iNOS and IL-1beta mRNA in livers. Furthermore, we addressed the effects of SAM on the protein C (PC) pathway, closely linked with sepsis. In CLP-induced septic mice, SAM elevated the impaired expression of PC mRNA in livers. In vitro, SAM reversed the decreased expressions of thrombomodulin (TM) and endothelial PC receptor (EPCR) mRNA induced by lipopolysaccharide (LPS) in endothelial cells. These findings suggest that SAM is able to restore the impaired protein C pathway. Taken together, the current study demonstrates that SAM has protective effects on polymicrobial sepsis in mice. The mechanisms of action involve anti-inflammation and upregulation of the PC pathway.

Eur J Pharmacol. 2009 Jun 17; Tao R, Ye F, He Y, Tian J, Liu G, Ji T, Su YThis study was to explore the effects of a compound (BPG) from Balanophora polyandra Griff on metabolic syndrome in mice. The animal model, developed obesity, dyslipidemia and insulin resistance, were induced by high-fat-diet in C57BL/6 mice, and were treated orally with 100 mg/kg/day BPG and 15 mg/kg/day rosiglitazone, respectively. The age-matched C57BL/6 mice fed with standard chow were used as normal control. The blood glucose, the value of serum triglyceride and the content of triglyceride in the skeletal muscle were determined by biochemical methods. The protein expression was evaluated by western blot. BPG administration decreased body weight gain, adiposity index, serum triglyceride levels, and triglyceride accumulation in skeletal muscle significantly. At the same time, BPG administration also exhibited extensive effects on insulin resistance by improving orally glucose tolerance test, insulin tolerance test and glucose infusion rate in hyperinsulinemic-euglycemic clamp test. Furthermore, in skeletal muscle, BPG revered the defect expression of IRbeta, IRS-1 and PTP1B, and also decreased the expression of ACCbeta and increased the expression of p-AMPK in the high-fat-die-induced mice. All the results suggest that BPG improves metabolic syndrome may by the enhancement of insulin sensitivity and fatty acid oxidation.