Sensitive analysis and simultaneous assessment of pharmacokinetic properties of crocin and crocetin after oral administration in rats.
Zhang Yue,Fei Fei,Zhen Le,Zhu Xuanxuan,Wang Jiankun,Li Sijia,Geng Jianliang,Sun Runbin,Yu Xiaoyi,Chen Tingting,Feng Siqi,Wang Pei,Yang Na,Zhu Yejin,Huang Jingqiu,Zhao Yuqing,Aa Jiye,Wang Guangji
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
Crocin and crocetin in rat plasma were simultaneously analysed using ultra-performance liquid chromatography tandem mass spectroscopy (UPLC-MS/MS), and method was fully validated. For the first time, levels of both crocin and crocetin in plasma were profiled after oral administration of crocin, and this UPLC-MS/MS approach was applied to evaluate pharmacokinetics and relative bioavailability of crocin and crocetin in rats. It was shown that crocin transformed into crocetin quickly in the gastrointestinal tract, and crocetin was 56-81 fold higher exposed in rat plasma than crocin after oral administration of crocin. A comparison study revealed that an oral administration of equal molar crocin achieved higher exposure of crocetin in rat plasma than that of crocetin. It was suggested that oral administration of crocin has the advantages over crocetin, and crocetin may be the active component potentially responsible for the pharmacological effect of crocin.
10.1016/j.jchromb.2016.12.003
Sensitive analysis and pharmacokinetic study of epalrestat in C57BL/6J mice.
Huang Jingqiu,Sun Runbin,Feng Siqi,He Jun,Fei Fei,Gao Haoxue,Zhao Yuqing,Zhang Yue,Gu Huilin,Aa Jiye,Wang Guangji
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
Epalrestat is clinically applied for the management of diabetic peripheral neuropathy, yet its pharmacokinetic properties are not well understood. In this study, a rapid and sensitive LC-MS/MS method was established for assaying epalrestat in bio-samples of mice. The method was validated and it showed a good linearity over the range of 2-5000ng/mL, a precision of less than 12.3%, and recovery and matrix effects of 112.5-123.6% and 87.9-89.5%, respectively. After administration of a single dose of epalrestat administered, the exposure level of AUC was positively dose-dependent and the mean C, AUC, T, and MRT were 36.23±7.39μg/mL, 29,086.5μg/Lh, 1.2h and 1.8h, respectively. Epalrestat was highly exposed in stomach, intestine, liver and kidney, and only a small amount was detected in brain, urine and feces. Multi-dose of epalrestat significantly increased MRT and apparent volume of distribution (V) relative to those of a single-dose.
10.1016/j.jchromb.2017.03.040
Application of liquid chromatography-tandem mass spectrometry to study the effect of docetaxel on pharmacokinetics and tissue distribution of apatinib in mice.
Feng Siqi,Zhang Jingwei,Wang Ying,Sun Runbin,Feng Dong,Peng Ying,Yang Na,Zhang Yue,Gao Haoxue,Gu Huilin,Wang Guangji,Aa Jiye,Zhou Fang
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
Apatinib, a highly selective small-molecule inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2), has attracted many attentions due to its anticancer activity in various malignancies containing non-small-cell lung cancer (NSCLC). Our previous preclinical study confirmed the enhanced anti-tumor efficacy of combined treatment between apatinib and docetaxel for NSCLC. However, the effects of docetaxel on pharmacokinetics and tissue distribution of apatinib are not clear. In present study, a reliable HPLC-MS/MS method was established for determination of apatinib. This method had a good linearity in the range of 1-5000 ng/mL, and the recovery and matrix effect were 100.1-103.5%, 77.6-83.5%, respectively. Plasma exposure level of apatinib and the values of C, AUC, T, and MRT were not affected by multi-dose of docetaxel. The tissue distributions (kidney, heart, lung, spleen) of apatinib in combined treatment group were lower at 0.25 h but higher at 2 h, and that in intestine and liver were not significantly changed compared with control group. However, pre-treatment with docetaxel had no significant effect on AUC of apatinib in tissues in mice. In conclusion, plasma and tissues exposure levels of apatinib were not affected by long-termed treatment with docetaxel, indicating that docetaxel is less likely to increase the side effect of apatinib such as hypertension, hand-foot syndrome and so on.
10.1016/j.jchromb.2018.03.017
Metabolomic Profiling Reveals That Reprogramming of Cerebral Glucose Metabolism Is Involved in Ischemic Preconditioning-Induced Neuroprotection in a Rodent Model of Ischemic Stroke.
Geng Jianliang,Zhang Yue,Li Sijia,Li Shuning,Wang Jiankun,Wang Hong,Aa Jiye,Wang Guangji
Journal of proteome research
Ischemic tolerance renders the brain resistant to ischemia-reperfusion (I/R) injury as a result of the activation of endogenous adaptive responses triggered by various types of preconditioning. The complex underlying metabolic mechanisms responsible for the neuroprotection of cerebral ischemic preconditioning (IPC) remain elusive. Herein, gas chromatography-mass spectrometry (GC-MS) technique was applied to delineate the dynamic changes of brain metabolome in a rodent model of ischemic stroke (transient occlusion of the middle cerebral artery, tMCAO), alone or after pretreatment with nonlethal ischemic tolerance induction (transient occlusion of the bilateral common carotid arteries, tBCCAO). Metabolomic analysis showed that accumulation of glucose (concentration increased more than 4 fold) and glycolytic intermediates is the prominent feature of brain I/R-induced metabolic disturbance. IPC attenuated brain I/R damage by subduing postischemic hyperglycolysis, increasing the pentose phosphate pathway (PPP) flux and promoting the utilization of β-hydroxybutyrate. The expression analysis of pivotal genes and proteins involved in relevant metabolic pathways revealed that the downregulation of AMP-activated protein kinase (AMPK)-mediated glucose transporter-1 (GLUT-1) and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) and reduced mRNA levels of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) subunits were associated with IPC-induced metabolic flexibility, which allows the brain to be more capable of withstanding severe I/R insults. The present study provided mechanistic insights into the metabolic signature of IPC and indicated that adaptively modulating brain glucose metabolism could be an effective approach for the therapeutic intervention of ischemic stroke.
10.1021/acs.jproteome.8b00339
Reduced Neuronal cAMP in the Nucleus Accumbens Damages Blood-Brain Barrier Integrity and Promotes Stress Vulnerability.
Zhang Yue,Lu Wuhuan,Wang Zibin,Zhang Ran,Xie Yuan,Guo Suhan,Jiao Li,Hong Yu,Di Zizhen,Wang Guangji,Aa Jiye
Biological psychiatry
BACKGROUND:Studies have suggested that chronic social stress specifically downregulates endothelial tight junction protein expression in the nucleus accumbens (NAc), thus increasing blood-brain barrier (BBB) permeability and promoting depression-like behaviors. However, the molecular mechanism underlying the reduction in tight junction protein, particularly in the NAc, is largely uncharacterized. METHODS:We performed comparative metabolomic profiling of the nucleus accumbens, prefrontal cortex, and hippocampus of social defeat-stressed mice to identify the molecular events that mediate BBB breakdown. RESULTS:We identified the levels of cyclic adenosine monophosphate (cAMP) that were specifically reduced in the NAc and positively correlated with the degree of social avoidance. Replenishing cAMP in the NAc was sufficient to improve BBB integrity and depression-like behaviors. We further found that cAMP levels were markedly decreased in neurons of the NAc, rather than in endothelial cells, astrocytes, or microglia. RNA-sequencing data showed that adenylate cyclase 5 (Adcy5), an enzyme responsible for the synthesis of cAMP from adenosine triphosphate (ATP), was predominantly expressed in the NAc; it also resided exclusively in neurons. Endogenous modulation of cAMP synthesis in neurons through the knockdown of Adcy5 in the NAc regulated the sensitivity to social stress. Moreover, deficient neuronal cAMP production in the NAc decreased the expression of reelin, while supplementary injection of exogenous reelin into the NAc promoted BBB integrity and ameliorated depression-like behaviors. CONCLUSIONS:Chronic social stress diminished cAMP synthesis in neurons, thus damaging BBB integrity in the NAc and promoting stress vulnerability. These results characterize neuron-produced cAMP in the NAc as a biological mechanism of neurovascular pathology in social stress.
10.1016/j.biopsych.2019.09.027
Orally Administered Crocin Protects Against Cerebral Ischemia/Reperfusion Injury Through the Metabolic Transformation of Crocetin by Gut Microbiota.
Frontiers in pharmacology
Our pilot study suggested that orally administered crocin was hardly absorbed into circulatory system, but it was effective against cerebral ischemic/reperfusion (I/R) injury. The pharmacologically active component and targeting site of crocin remain elusive. In this study, the cerebral-protective effect of crocin was evaluated on a rat transient middle cerebral artery occlusion (MCAO) model. Our data showed that oral administration of crocin had better effectiveness in cerebral protection than an intravenous injection. Neither crocin nor its metabolite crocetin were determined in the brain of cerebral I/R rats, indicating a target site of periphery. Abundant crocetin was detected in plasma after oral administration instead of intravenous injection of crocin. Meanwhile, orally administered crocetin showed similar cerebral protection to that of crocin, but this exciting effect was not clearly observed by intravenous administration of crocetin, indicating the importance of crocetin in gut. Moreover, orally administered crocin showed less cerebral-protective effect in pseudo germ-free (pGF) MCAO rats. and experiments confirmed that crocin could be deglycosylated to crocetin in gut content of normal rats, rather than that of pGF rats, indicating that gut microbiota facilitated the transformation of crocin into crocetin, which played a key role in the activation of the pharmacological effect. Metabolomic study revealed that microbial-host co-metabolic molecules were significantly perturbed after oral administration of crocin, indicating a regulation on intestinal ecosystem. It was further suggested that gut microbiota may be the potential target of the cerebral-protective effect of crocin.
10.3389/fphar.2019.00440