Pharmacokinetic studies of ginkgolide K in rat plasma and tissues after intravenous administration using ultra-high performance liquid chromatography-tandem mass spectrometry

Biomedical Chromatography

et al. 2018

Xuebijing injection (XBJI) is a traditional Chinese medicine prescription extracted from five Chinese herbs. Hydroxysafflor yellow A, oxypaeoniflorin, ferulic acid and benzoylpaeoniflorin are the main bioactive ingredients of XBJI. This paper presents an application of ultra-high-performance liquid chromatography-Q-exactive hybrid quadrupole-Orbitrap high-resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS) to quantify four compounds of XBJI in rats various tissues for tissue distribution studies. The analytes were separated on a Waters Acquity UHPLC ® BEH C 18 column with a gradient mobile phase consisting of acetonitrile-water (containing 0.1% formic acid) at a flow rate of 0.2 mL/min. Mass spectrometric detection was performed by parallel reaction monitoring via a heated electrospray ionization source under the negative ionization mode. The method was validated in various tissue samples, and has demonstrated great performance for rapidity, accuracy, high sensitivity and selectivity. It was successfully applied to the tissue distribution studies of XBJI after intravenous administration to rats. It was also the first study to investigate the tissue distribution of XBJI in rats and we found that the concentrations of four compounds were high in kidney, liver, stomach and intestine. The clinical use of XBJI should focus on its pharmacodynamics and safety studies in these tissues.

Section: Methodsmentioning

confidence: 99%

Tissue distribution profiles of multiple major bioactive components in rats after intravenous administration of Xuebijing injection by UHPLC–Q–Orbitrap HRMS

Zuo

Sun

Biomedical Chromatography

et al. 2018

“…A TCM may contain various complex ingredients, meaning that a method for separating, identifying and screening the activity of individual compounds is necessary to identify the multiple targets. Over the last 15 years, ultra‐performance liquid chromatography/quadrupole time‐of‐flight mass spectrometry (UPLC/Q‐TOF MS) has established itself as the primary and most accessible technique for the analysis and identification of TCM components in biological matrices owing to the improved sensitivity, greater resolution and higher speed compared with traditional HPLC, as well as the advantages of structural information derived from TOF‐MS technology for accurate mass determination (Fan et al ., ; Gao et al ., ). High‐throughput screening technology has been applied for the screening of active ingredients, which will be beneficial for the modernization of TCMs (Bai et al ., ; Liu et al ., ; Cheng et al ., ).…”

Section: Introductionmentioning

confidence: 99%

Screening and identification of Caulis Sinomenii bioactive ingredients with dual‐target NF‐κB inhibition and β_2‐AR agonizing activities

Sun

Han

Biomedical Chromatography

et al. 2016

Caulis Sinomenii (CS) is a valuable traditional medicine in China. Its extract can act as an anti-inflammatory agent and a vascular smooth muscle relaxant. However, the underlying mechanisms remain unknown. In this study, we developed a simple dual-target method based on ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry combined with a dual-target bioactive screening assay for anti-inflammatory and antispasmodic activities to characterize the chemical structure of various bioactive compounds of CS rapidly. Seven potential NF-κB inhibitors were identified, including laudanosoline-1-O-xylopyranose, 6-O-methyl-laudanosoline-1-O-glucopyranoside, menisperine, sinomenine, laurifoline, magnoflorine and norsinoacutin. Furthermore, IL-6 and IL-8 assays confirmed the anti-inflammatory effects of these potential NF-κB inhibitors, in which laudanosoline-1-O-d-xylopyranose and menisperine were revealed as novel NF-κB inhibitors. Among the seven identified alkaloids, three potential β -adrenergic receptor agonists, including sinomenine, magnoflorine and laurifoline, were characterized using a luciferase reporter system to measure for the activity of β -adrenergic receptor agonists. Finally, sinomenine, magnoflorine and laurifoline were identified not only as potential NF-κB inhibitors but also as potential β -adrenegic receptor agonists, which is the first time this has been reported. Molecular dynamic simulation and docking results suggest that the three dual-bioactive constituents could not only inhibit Pseudomonas aeruginosa PAK strain-induced inflammatory responses via a negative regulation of the Braf protein that participates in MAPK signaling pathway but also activate the β -adrenegic receptor. These results suggest that CS extract has dual signaling activities with potential clinical application as a novel drug for asthma.

“…As a derivative of GB, GK has been shown to possess protective effects on cerebral ischaemia/reperfusion injury (Ma et al , ) and markedly protect PC12 cells against H 2 O 2 ‐ or glutamate‐induced cytotoxicity by ameliorating mitochondrial dysfunction, oxidative stress and Ca 2 + overload (Ma et al , ; Ma et al , ). A pharmacokinetic study of GK in rats provided some important information that would promote further study of GK in human diseases (Fan et al , ). However, the effects of GK on ER stress remain undefined.…”

Section: Introductionmentioning

confidence: 99%

Ginkgolide K protects the heart against endoplasmic reticulum stress injury by activating the inositol‐requiring enzyme 1α/X box‐binding protein‐1 pathway

Wang²,

Fan

et al. 2016

British J Pharmacology

*These two authors contributed equally to this work. BACKGROUND AND PURPOSEEndoplasmic reticulum (ER) stress is increasingly recognized as an important causal factor of many diseases. Targeting ER stress has now emerged as a new therapeutic strategy for treating cardiovascular diseases. Here, we investigated the effects and underlying mechanism of ginkgolide K (1,10-dihydroxy-3,14-didehydroginkgolide, GK) on cardiac ER stress. EXPERIMENTAL APPROACHCell death, apoptosis and ER stress-related signalling pathways were measured in cultured neonatal rat cardiomyocytes, treated with the ER stress inducers tunicamycin, hydrogen peroxide and thapsigargin. Acute myocardial infarction was established using left coronary artery occlusion in mice, and infarct size was measured by triphenyltetrazolium chloride staining. Echocardiography was used to assess heart function and transmission electron microscopy for evaluating ER expansion. KEY RESULTSGinkgolide K (GK) significantly decreased ER stress-induced cell death in both in vitro and in vivo models. In ischaemic injured mice, GK treatment reduced infarct size, rescued heart dysfunction and ameliorated ER dilation. Mechanistic studies revealed that the beneficial effects of GK occurred through enhancement of inositol-requiring enzyme 1α (IRE1α)/X box-binding protein-1 (XBP1) activity, which in turn led to increased ER-associated degradation-mediated clearance of misfolded proteins and autophagy. In addition, GK was also able to partly repress the pro-apoptotic action of regulated IRE1-dependent decay and JNK pathway. CONCLUSIONS AND IMPLICATIONSIn conclusion, GK acts through selective activation of the IRE1α/XBP1 pathway to limit ER stress injury. GK is revealed as a promising therapeutic agent to ameliorate ER stress for treating cardiovascular diseases. AbbreviationsASK1, apoptotic signalling kinase-1; ATF4, activating transcription factor 4; ATF6, activating transcription factor 6; CHOP, C/EBP homologous protein; ER, endoplasmic reticulum; ERAD, ER-associated degradation; eIF2α, eukaryotic translation initiation factor 2α; GB, ginkgolide B; GK, ginkgolide K; GRP78, glucose-regulated protein 78 kD; IRE1α, inositol-requiring enzyme 1α; NRCMs, neonatal rat cardiomyocytes; PERK, pancreatic eIF2α kinase; RIDD, regulated IRE1-dependent decay; TRAF2, TNF receptor-associated factor 2; UPR, unfolded protein response; XBP1, X box-binding protein-1 BJP IntroductionThe endoplasmic reticulum (ER) is a membranous organelle that plays an important role in the maintenance of cellular processes such as protein processing, calcium homeostasis and lipid biosynthesis. Effective ER function is essential for the folding of secretory and membrane proteins (Wei and Hendershot, 1996). A number of cellular stresses disturb the balance between the folding capacity of the ER and the burden of incoming proteins, including oxidative stress, ischaemic insult, abnormal ER calcium content, and enhanced expression of normal and/or folding-defective proteins. These events lead to the accumulation of unfo...