Xyloketal B Attenuates Fatty Acid-Induced Lipid Accumulation via the SREBP-1c Pathway in NAFLD Models.

The goal of this study was to examine the effects of xyloketal B on nonalcoholic fatty liver disease (NAFLD) and to explore the molecular mechanisms underlying its effects in both in vivo and in vitro models. We discovered an association between xyloketal B and the sterol regulatory element-binding protein-1c (SREBP-1c) signaling pathway, which is related to lipid metabolism. Mice were dosed with xyloketal B (5, 10 and 20 mg/kg/d) and atorvastatin (15 mg/kg/d) via intraperitoneal injection once daily for 40 days after being fed a high fat diet plus 10% high fructose liquid (HFD+HFL) for 8 weeks. Xyloketal B significantly improved HFD+HFL-induced hepatic histological lesions and attenuated lipid and glucose accumulation in the blood as well as lipid accumulation in the liver. Xyloketal B increased the expression of CPT1A, and decreased the expression of SREBP-1c and its downstream targeting enzymes such as ACC1, ACL, and FAS. Xyloketal B also significantly reduced lipid accumulation in HepG2 cells treated with free fatty acids (FFAs). These data suggested that xyloketal B has lipid-lowering effects via the SREBP-1c pathway that regulate lipid metabolism. Thus, targeting SREBP-1c activation with xyloketal B may be a promising novel approach for NAFLD treatment.

[Optimization of Formulation of Panax notoginseng Saponins Transfersomes].

OBJECTIVE: To optimize the formulation of Panax notoginseng saponins (PNS) transfersomes. METHODS: PNS transfersomes were prepared by film hydration-dispersion process. Based on the entrapment efficiency (EE) of ginsenoside Rg1 and ginsenoside Rb1, the effects of formulated quantity of sodium deoxycholate and cholesterol, the relative ion strength and pH value of hydration liquid were investigated. The formulation of PNS transfersomes were optimized by single-factor experiment and uniform design experiment. The in vitro characteristics of the optimized transfersomes were evaluated. RESULTS: The optimum formulation were as follows: egg phospholipid 0.45 g, cholesterol 0.05 g,vitamin E 0.01 g, sodium deoxycholate 0.119 g, PNS 0.1 g,10 mL of hydration liquid with pH at 4.75 (a mixture of 0.1 mol/L citric acid solution and 0.2 mol/L disodium orthophosphate solution, which corresponded to appropriate ion strength). The optimized PNS transfersomes had an average size of (121.8 ± 3.9) nm with a PDI of 0.136 ± 0.007 and a Zeta potential of (-8. 24 ± 0. 63) mV. The EE of ginsenoside Rg1 and ginsenoside Rb1 was 88.0% and 98.7% respectively. CONCLUSION: The formulation of PNS transfersomes can be optimized by uniform design experiment combined with single-factor experiment.

MicroRNA-134-3p is a novel potential inhibitor of human ovarian cancer stem cells by targeting RAB27A.

The cluster of microRNAs (miRNAs) in the DLK1-DIO3 genomic imprinted region contains several miRNAs that have a significant regulatory role in tumor proliferation and invasion. One of these miRNAs is miR-134-3p, and its expression changes significantly in human ovarian cancer stem cells (OCSCs) and in CD44-/CD133- ovarian cancer. The results of a luciferase assay showed that miR-134-3p silenced RAB27A by binding to the 3'-UTR of RAB27A mRNA. Overexpression of miR-134-3p in human OCSCs can not only inhibit the expression of RAB27A but also can effectively downregulate the expression of some tumor proliferation and invasion genes. Overexpression of miR-134-3p can not only inhibit the in vitro proliferation and cell cycle progression of human OCSCs but also can decrease the tumorigenicity in nude mice.

Xyloketal B, a marine compound, acts on a network of molecular proteins and regulates the activity and expression of rat cytochrome P450 3a: a bioinformatic and animal study.

Natural compounds are becoming popular for the treatment of illnesses and health promotion, but the mechanisms of action and safety profiles are often unknown. Xyloketal B (XKB) is a novel marine compound isolated from the mangrove fungus Xylaria sp., with potent antioxidative, neuroprotective, and cardioprotective effects. However, its molecular targets and effects on drug-metabolizing enzymes are unknown. This study aimed to investigate the potential molecular targets of XKB using bioinformatic approaches and to examine the effect of XKB on the expression and activity of rat cytochrome P450 3a (Cyp3a) subfamily members using midazolam as a model probe. DDI-CPI, a server that can predict drug-drug interactions via the chemical-protein interactome, was employed to predict the targets of XKB, and the Database for Annotation, Visualization and Integrated Discovery (DAVID) was used to analyze the pathways of the predicted targets of XKB. Homology modeling was performed using the Discovery Studio program 3.1. The activity and expression of rat hepatic Cyp3a were examined after the rats were treated with XKB at 7 and 14 mg/kg for 8 consecutive days. Rat plasma concentrations of midazolam and its metabolite 1'-OH-midazolam were determined using a validated high-performance liquid chromatographic method. Bioinformatic analysis showed that there were over 324 functional proteins and 61 related signaling pathways that were potentially regulated by XKB. A molecular docking study showed that XKB bound to the active site of human cytochrome P450 3A4 and rat Cyp3a2 homology model via the formation of hydrogen bonds. The in vivo study showed that oral administration of XKB at 14 mg/kg to rats for 8 days significantly increased the area under the plasma concentration-time curve (AUC) of midazolam, with a concomitant decrease in the plasma clearance and AUC ratio of 1'-OH-midazolam over midazolam. Further, oral administration of 14 mg/kg XKB for 8 days markedly reduced the activity and expression of hepatic Cyp3a in rats. Taken together, the results show that XKB could regulate networks of molecular proteins and related signaling pathways and that XKB downregulated hepatic Cyp3a in rats. XKB might cause drug interactions through modulation of the activity and expression of Cyp3a members. More studies are warranted to confirm the mechanisms of action of XKB and to investigate the underlying mechanism for the regulating effect of XKB on Cyp3a subfamily members.

A validated high-performance liquid chromatographic method with diode-array detection for the estimation of xyloketal B in rat plasma.

A sensitive and specific HPLC-UV method was developed and validated for the determination of xyloketal B in rat plasma. Following liquid-liquid extraction, the separation was performed using an isocratic mobile phase of methanol-acetonitrile-water (30/30/40, v/v/v) on a Phenomenex C(18) column (4.6mm×250mm, 5µm). The eluent was monitored at 220nm and at a flow rate of 0.8mlmin(-1). A linear curve over the concentration range of 1-128µg/ml (r>0.999) was established. The LLOQ of the method was 1µg/ml. Good precision and accuracy at concentrations of 2.5, 25 and 100µg/ml were obtained. The recovery of xyloketal B in plasma was >87.91%. The validated method was found to be specific, precise and accurate in the study. The analytic method was satisfactorily applied to perform preclinical pharmacokinetic study of xyloketal B in rat plasma.