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Objective: To explore the hypolipidemic activity and toxic side effect of lansiumamide B (LB) from chicken-heart shaped wampee (Clausena lansium) seeds in C57BL/6J mice fed on a high-fat-diet (HFD) model. Methods: The no observed adverse effect level (NOAEL) of LB in mice was assessed by oral acute toxicity test. HFD-fed mice were intragastrically administered with LB at 1/100, 1/50 and 1/25 NOAEL for 4 weeks. To evaluate the lipid-lowering activity of LB, body mass, serum lipids, insulin resistance, and oxidative stress indicators were measured. Results: The NOAEL of LB was 2 g/kg mb. LB significantly reduced body mass in HFD-fed mice. Compared with the HFD model group, body mass decreased by 15.51% and Lee’s index declined by 3.25% in the high-dose LB group; the concentration of high-density lipid-cholesterol (HDL-C) increased by 38.04%, and the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) in the serum increased by 41.86%, 41.95%, and 105.50%, respectively. Conclusion: LB within the NOAEL range has significant lipid-lowering activity in mice without obvious toxicity.

6-Gingerol is the major pungent component in ginger. It possesses a variety of health benefits including antitumor, anti-inflammatory and antioxidant, hypoglycemic, hypolipidemic and hypotensive activities as well as colitis prevention and treatment. However, the health effects of oral 6-gingerol are limited due to the low water solubility, poor gastrointestinal stability, rapid metabolism in the body, release at non-target sites, and pungent and bitter taste. In this article, the health effects of 6-gingerol including anticancer, anti-inflammatory and hypolipidemic activity, and preventing and treating cardiovascular and cerebrovascular diseases as well as gastrointestinal diseases are reviewed together with the underlying mechanisms. Based on a review of recent progress in the research on the gastrointestinal absorption of 6-gingerol, its distribution, metabolism and excretion in the systematic circulation and its metabolic processes in the upper and lower gastrointestinal tract, the current status of the design and development of oral delivery systems for 6-gingerol. The mechanism for the enhancing effect of delivery systems on the health benefits of 6-gingerol and the design principle of the strategies to enhance the health benefits of 6-gingerol are elucidated. Hopefully, this review will not only provide a theoretical guidance for the design of oral delivery systems for 6-gingerol and the research on the mechanism for the enhancing effect of oral delivery systems on the health benefits of 6-gingerol, but also provide scientific evidence for the design of 6-gingerol-based functional foods.

1-(4-(Pyrrolidin-1-yl-methyl)phenyl)-3-(4-((3-(trifluoromethyl) phenyl)amino)quinazolin-6-yl)urea (ZCJ14), a novel epidermal growth factor receptor (EGFR) inhibitor, with diarylurea moiety, displays anticancer effect. In the present study, an LCMS/MS method was established to determine the concentration of ZCJ14 in rat plasma. Furthermore, the method was applied to investigate the pharmacokinetic characteristics of ZCJ14. Chromatographic separation of ZCJ14 and internal standard (IS) [1-phenyl-3-(4-((3-(trifluoromethyl)phenyl)amino) quinazolin-6-yl)urea] was accomplished by gradient elution using the Kromasil C18 column. The selected reaction monitoring transitions were performed at m/z 507.24→436.18 and 424.13→330.96 for ZCJ14 and IS, resp. The established method was linear over the concentration range of 10–1000 ng mL−1. The intra- and inter-day precisions were < 11.0 % (except for LLOQ which was up to 14.3 %) and the respective accuracies were within the range of 87.5–99.0 %. The extraction recovery and matrix effect were within the range of 88.4–104.5 % and 87.3–109.9 %, resp. ZCJ14 was stable under all storage conditions. The validated method was successfully applied to the pharmacokinetic study of ZCJ14 in rats, and the pharmacokinetic parameters have been determined. The oral bioavailability of ZCJ14 was found to be 46.1 %. Overall, this accurate and reliable quantification method might be useful for other diarylurea moiety-containing drugs.

Abstract Background Cigarette smoking enhances the risk of stroke. However, the underlying molecular mechanisms are largely unknown. The present study established an in vivo rat secondhand cigarette smoking (SHS) model and examined the hypothesis that SHS upregulates endothelin receptors with increased cerebrovascular contraction via the Raf/extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinases (MAPK) pathway. Results Rats were exposed to SHS for up to 8 weeks. The cerebral artery vasoconstriction was recorded by a sensitive myograph. The mRNA and protein expressions for endothelin receptors in cerebral arteries were studied by real-time PCR and Western blot. Compared to fresh air exposed rats, cerebral arteries from SHS rats exhibited stronger contractile responses (P < 0.05) mediated by endothelin type A (ETA) receptors. The expressions of mRNA and protein for ETA receptors in the cerebral arteries from SHS rats were higher (P < 0.05) than that in control. SHS did not affect endothelin type B (ETB) receptor-mediated contractions, mRNA or protein levels. The results suggest that SHS upregulates ETA, but not ETB receptors in vivo. After SHS exposure, the mRNA levels of Raf-1 and ERK1/2, the protein expression of phosphorylated (p)-Raf-1 and p-ERK1/2 were increased (P < 0.05). Raf-1 inhibitor, GW5074 suppressed the enhanced ETA receptor-mediated contraction, mRNA and protein levels induced by SHS. In addition, GW5074 inhibited the SHS-caused increased mRNA and phosphorylated protein levels of Raf-1 and ERK1/2, suggesting that SHS induces activation of the Raf/ERK/MAPK pathway. Conclusions SHS upregulates cerebrovascular ETA receptors via the Raf/ERK/MAPK pathway, which provides novel understanding of mechanisms involved in SHS-associated stroke.

Abstract Background Sidestream smoke is closely associated with airway inflammation and hyperreactivity. The present study was designed to investigate if the Raf-1 inhibitor GW5074 and the anti-inflammatory drug dexamethasone suppress airway hyperreactivity in a mouse model of sidestream smoke exposure. Methods Mice were repeatedly exposed to smoke from four cigarettes each day for four weeks. After the first week of the smoke exposure, the mice received either dexamethasone intraperitoneally every other day or GW5074 intraperitoneally every day for three weeks. The tone of the tracheal ring segments was recorded with a myograph system and concentration-response curves were obtained by cumulative administration of agonists. Histopathology was examined by light microscopy. Results Four weeks of exposure to cigarette smoke significantly increased the mouse airway contractile response to carbachol, endothelin-1 and potassium. Intraperitoneal administration of GW5074 or dexamethasone significantly suppressed the enhanced airway contractile responses, while airway epithelium-dependent relaxation was not affected. In addition, the smoke-induced infiltration of inflammatory cells and mucous gland hypertrophy were attenuated by the administration of GW5074 or dexamethasone. Conclusion Sidestream smoke induces airway contractile hyperresponsiveness. Inhibition of Raf-1 activity and airway inflammation suppresses smoking-associated airway hyperresponsiveness.

Abstract Background Cigarette smoking is a strong risk factor for vascular disease and known to cause dysfunction of the endothelium. However, the molecular mechanisms involved are still not fully understood. Methods In order to reveal the direct effects of lipid-soluble smoke particles on the endothelium, ring segments isolated from rat mesenteric arteries and human middle cerebral arteries (MCA) obtained at autopsy were incubated for 6 to 48 hrs in the presence of dimethylsulphoxide (DMSO)-soluble particles from cigarette smoke (DSP), i.e. lipid-soluble smoke particles. The endothelial microstructure was examined by transmission electron microscopy. The endothelial function was evaluated by acetylcholine (ACh)-induced endothelium-dependent vasodilatation, using a sensitive myograph. Results After DSP treatment, the arterial endothelium was swollen and loosing its attachment. In functional tests, the total ACh-induced dilatation, the nitric oxide (NO)-mediated and the endothelium-derived hyperpolarization factor (EDHF)-mediated dilatations were significantly decreased by DSP in a time- and concentration-dependent manner (p < 0.05). Nicotine, an important compound in cigarette smoke had, in an equivalent concentration as in DSP, no such effects (p > 0.05). Similar results were obtained in the human MCA. Conclusion Thus, we demonstrate that the lipid-soluble smoke particles, but not nicotine, caused damage to arterial endothelium and reduced the endothelium-dependent dilatation in man and rat.

The severe adverse reaction to vitamin K1 injection is always remarkable and is thought to result from anaphylaxis. Paradoxically, however, some patients administered vitamin K1 injection for the first time have adverse reactions. Using beagle dogs, the present study tested the hypothesis that the response to vitamin K1 is an anaphylactoid reaction. The results showed that serious anaphylaxis-like symptoms appeared in beagle dogs after the administration of vitamin K1 injection for the first time. The plasma histamine concentration increased, and blood pressure decreased sharply. After sensitization, dogs were challenged with vitamin K1 injection and displayed the same degree of symptoms as prior to sensitization. However, when the vitamin K1 injection-sensitized dogs were challenged with a vitamin K1-fat emulsion without solubilizers such asTween-80, the abnormal reactions did not occur. Furthermore, there was no significant change in the plasma immunoglobulin E concentration after vitamin K1 challenge. Following treatment with vitamin K1 injection, the release of histamine and β-hexosaminidase by rat basophilic leukemia-2H3 cells as well as the rate of apoptosis increased. The Tween-80 group displayed results similar to those observed following vitamin K1 injection in vivo. However, the dogs in the vitamin K1-fat emulsion group did not display any abnormal behavior or significant change in plasma histamine. Additionally, degranulation and apoptosis did not occur in rat basophilic leukemia-2H3 cells. Our results indicate that the adverse reaction induced by vitamin K1 injection is an anaphylactoid reaction, not anaphylaxis. Vitamin K1 injection induces the release of inflammatory factors via a non-IgE-mediated immune pathway, for which the trigger may be the solubilizer. [ABSTRACT FROM AUTHOR]