Turning Non-Emissive Schiff Bases Into Aggregate Emitters.

Schiff bases are a crucial component in various functional materials but often exhibit non-emissive behavior which significantly limits their potential applications as luminescent materials. However, traditional approaches to convert them into aggregate emitters often require intricate molecular design, tedious synthesis, and significant time and resource consumption. Herein, we present a cocrystallization-induced emission strategy that can transform non-emissive (hetero)aryl-substituted Schiff bases into green-yellow to yellow aggregate emitters via even simple grinding of a mixture of Schiff bases and 1,2,4,5-tetracyanobenzene (TCB) mixtures. The combined experimental and theoretical analysis revealed that the cocrystallization inhibits the C=N isomerization and promotes face-to-face π-π interaction, which restricts access to both the dark state and canonical intersection to ultimately induce emission. Furthermore, the induced emission enables the observation of solid-state molecular diffusion through fluorescence signals, advancing white light emission diodes, and notably, solution-processed organic light-emitting diodes based on cocrystal for the first time. This study not only highlights the potential of developing new C=N structural motifs for AIEgens but also could boost advancements in related structure motifs like C=C and N=N.

Conformational cycle of human polyamine transporter ATP13A2.

Dysregulation of polyamine homeostasis strongly associates with human diseases. ATP13A2, which is mutated in juvenile-onset Parkinson's disease and autosomal recessive spastic paraplegia 78, is a transporter with a critical role in balancing the polyamine concentration between the lysosome and the cytosol. Here, to better understand human ATP13A2-mediated polyamine transport, we use single-particle cryo-electron microscopy to solve high-resolution structures of human ATP13A2 in six intermediate states, including the putative E2 structure for the P5 subfamily of the P-type ATPases. These structures comprise a nearly complete conformational cycle spanning the polyamine transport process and capture multiple substrate binding sites distributed along the transmembrane regions, suggesting a potential polyamine transport pathway. Integration of high-resolution structures, biochemical assays, and molecular dynamics simulations allows us to obtain a better understanding of the structural basis of how hATP13A2 transports polyamines, providing a mechanistic framework for ATP13A2-related diseases.

Engineering Platelets with PDL1 Antibodies and Iron Oxide Nanoparticles for Postsurgical Cancer Immunotherapy.

Recently, immune checkpoint blockade (ICB) therapy has achieved great success in inhibition of the recurrence and metastasis of tumor. However, this therapy is challenged by the poor delivery efficiency of ICB agents and the insufficient activation of antitumor immunity by ICB only. Here, we describe a strategy using platelets as carriers for co-delivery of ICB agents (anti-PDL1 antibodies, aPDL1) and photothermal agents (iron oxide nanoparticles, IONPs) to the postsurgical tumor site, which simultaneously provides photothermal therapy for ablation of residual tumor cells and ICB therapy for blocking the immunoinhibitory signals in the tumor microenvironment. We engineered platelets by chemical conjugation of aPDL1 and physical adsorption of IONPs on the surfaces of the platelets. Once they were adhered to the subendothelium of the surgical site, engineered platelets (P-P-IO) were activated and released aPDL1 and IONPs to the surrounding tissue. Upon laser irradiation, mild photothermal therapy (PTT) induces necrosis of residual tumor cells, producing tumor-associated antigens to generate innate immune responses. The co-delivered aPDL1 leads to efficient antitumor immunity, as evidenced by the reduced recurrence of the residual tumor and improved infiltration of both CD4+ and CD8+ T cells in a postsurgical breast tumor xenograft mouse model. We believe our strategy holds great promise in the clinic for combating postsurgical cancer recurrence.

Layer-by-Layer Assembly of Lipid Nanobubbles on Microneedles for Ultrasound-Assisted Transdermal Drug Delivery.

Microneedles as a typical device for transdermal drug delivery provide an alternative route for drug administration with minimal digestion by organs and better patient compliance. However, diffusion of passively released drug molecules within the skin tissue mainly depends on the interstitial fluid, which may be affected by different physiological conditions of individuals. Herein, we propose a nanobubble-modified microneedle patch for ultrasound-assisted drug delivery, which provides additional driving force for penetration and diffusion of the drug molecules. Layer-by-layer self-assembled drug-containing nanobubbles on the surfaces of microneedles trigger active drug release upon application of ultrasound. The concomitant microstreaming caused by cavitation effects facilitates the penetration and diffusion of drug molecules in the gelatin gel model and the ex vivo porcine skin model. The proposed drug delivery strategy holds great promise for rapid transdermal drug delivery with enhanced penetration and diffusion of the released drugs.

Ag-Catalyzed Asymmetric Interrupted Barton-Zard Reaction Enabling the Enantioselective Dearomatization of 2- and 3-Nitroindoles.

We disclose a Ag-catalyzed asymmetric interrupted Barton-Zard reaction of α-aryl-substituted isocyanoacetates with 2- and 3-nitroindoles, which enables the dearomatization of nitroindoles and hence offers rapid access to an array of optically active tetrahydropyrrolo[3,4-b]indole derivatives bearing three contiguous stereogenic centers, including two tetrasubstituted chiral carbon atoms with pretty outcomes (up to 99% yield, 91:9 dr, and 96% ee). The synthetic potential of the protocol was showcased by the gram-scale reaction and versatile transformations of the product.

Fasting augments pyrrolizidine alkaloid-induced hepatotoxicity.

Pyrrolizidine alkaloids (PAs) are phytotoxins widely present in various natural products and foodstuffs. The present study aims to investigate the effects of fasting on PA-induced hepatotoxicity and the underlying biochemical mechanisms. The results of hepatotoxic study showed that 15-h overnight fasting significantly exacerbated the hepatotoxicity of retrorsine (RTS, a representative toxic PA) in fasted rats compared to fed rats, as indicated by remarkably elevated plasma ALT and bilirubin levels and obvious liver histological changes. Further toxicokinetic studies revealed that fasting significantly enhanced cytochromes P450 enzymes (CYPs)-mediated metabolic activation of RTS leading to increased formation of pyrrole-protein adducts and thus decreased the in vivo exposure and excretion of both parent RTS and its N-oxide metabolite. Metabolic studies demonstrated that fasting induced enzyme activities of CYP1A2, CYP2B6 and CYP2E1 that participated in catalyzing RTS to its reactive pyrrolic metabolites. Moreover, fasting also dramatically decreased hepatic glutathione (GSH) content, which restricted the detoxification of GSH by neutralizing the reactive pyrrolic metabolite of RTS, further contributing to the enhanced hepatotoxicity. The present findings may have an impact on future PA toxicity tests with different dietary styles and/or risk assessment of metabolite-mediated toxins by considering the profound effects of fasting.

Multiple-relaxation-time finite-difference lattice Boltzmann model for the nonlinear convection-diffusion equation.

In this paper, a multiple-relaxation-time finite-difference lattice Boltzmann method (MRT-FDLBM) is developed for the nonlinear convection-diffusion equation (NCDE). Through designing the equilibrium distribution function and the source term properly, the NCDE can be recovered exactly from MRT-FDLBM. We also conduct the von Neumann stability analysis on the present MRT-FDLBM and its special case, i.e., single-relaxation-time finite-difference lattice Boltzmann method (SRT-FDLBM). Then, a simplified version of MRT-FDLBM (SMRT-FDLBM) is also proposed, which can save about 15% computational cost. In addition, a series of real and complex-value NCDEs, including the isotropic convection-diffusion equation, Burgers-Fisher equation, sine-Gordon equation, heat-conduction equation, and Schrödinger equation, are used to test the performance of MRT-FDLBM. The results show that both MRT-FDLBM and SMRT-FDLBM have second-order convergence rates in space and time. Finally, the stability and accuracy of five different models are compared, including the MRT-FDLBM, SMRT-FDLBM, SRT-FDLBM, the previous finite-difference lattice Boltzmann method [H. Wang, B. Shi et al., Appl. Math. Comput. 309, 334 (2017)10.1016/j.amc.2017.04.015], and the lattice Boltzmann method (LBM). The stability tests show that the sequence of stability from high to low is as follows: MRT-FDLBM, SMRT-FDLBM, SRT-FDLBM, the previous finite-difference lattice Boltzmann method, and LBM. In most of the precision test results, it is found that the order from high to low of precision is MRT-FDLBM, SMRT-FDLBM, SRT-FDLBM, and the previous finite-difference lattice Boltzmann method.

Chiral Indoline-2-carboxylic Acid Enables Highly Enantioselective Catellani-type Annulation with 4-(Bromomethyl)cyclohexanone.

Chiral indoline-2-carboxylic acid has been identified to enable a highly enantioselective Catellani-type annulation of (hetero)aryl, alkenyl triflate and conjugated vinyl iodides with 4-(bromomethyl)cyclohexanone, directly assembling a diverse range of chiral all-carbon bridged ring systems. Control experiments and DFT calculations suggest that the coordinating orientation of the chiral amino acid to the arylpalladium(II) center allows for high levels of stereochemical control.

Characterization of liver injury induced by a pyrrolizidine alkaloid in rats.

BACKGROUND: Pyrrolizidine alkaloids (PAs) are common phytotoxins. PA intoxication is reported to cause severe acute liver damage, typically known as hepatic sinusoidal obstruction syndrome (HSOS), but it remains obscure whether the acute liver damage may progress into chronic liver disease characterized by hepatic fibrosis. PURPOSE: This study aims to characterize the biochemical markers of liver injury and histological features of regressive and progressive liver fibrosis, and to examine changes in hepatic gene expression that may underpin mechanisms of fibrogenesis in rats induced by retrorsine (RTS), a representative toxic PA. STUDY DESIGN/METHODS: Rats were gavaged with RTS via two dosing regimens, i.e. a single dose of 40 mg/kg (Group 1) and two doses of 40 mg/kg and 20 mg/kg on day 0 and day 7 (Group 2), respectively. Rats receiving one (Group 3) or two (Group 4) doses of vehicle served as negative controls. The animals were followed for up to 16 weeks by serum biochemical analyses and histological examination, and gene expression assays of liver tissues. RESULTS: Acute liver injury on day 2 manifested as HSOS, characterized by sinusoidal dilation, endothelial cell damage, and elevated serum alanine aminotransferase activity and bilirubin levels. In Group 1, mild liver fibrosis developed at sinusoids and perisinusoidal space surrounding the central veins at week 1 and 2, and thereafter, all liver injury resolved gradually. In Group 2, liver fibrosis progressed within the 16-week observation period. No apparent liver injury was observed in Groups 3 and 4. Compared with negative control groups, RTS induced myofibroblastic activation, TGF-ß1 signaling, and changes in expression of matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1). These dynamic changes differed in Groups 1 and 2, corresponding with the regression and progression of liver fibrosis, respectively, in these groups. CONCLUSION: This study has provided in-vivo proof of concept that "one hit" and "two hits" of RTS lead to acute resolving liver injury and chronic progressive liver fibrosis, respectively. These animal models may serve as powerful tools for studying RTS toxicology and related preventive and therapeutic strategies and as positive controls for studying other PA- and non-PA-induced liver injury.

A new PLA-Tween composited drug-carrying C60-Fe3O4 multifunctional ultrasound contrast agent based on three kinds of lesions.

A PLA-Tween composited drug-carrying C60-Fe3O4 microbubble was designed and prepared. Using Fe3O4 as a targeting factor and C60 as a drug carrier, warfarin (WF), netimixin (NET) and doxorubicin (DOX) respectively were loaded on a C60-Fe3O4 complex through π-π conjugate effect, and C60-Fe3O4-WF, C60-Fe3O4-NET and C60-Fe3O4-DOX targeted drug-loading complexes were obtained. The three drug-loading complexes were respectively combined into PLA and Tween membrane material, PLA-Tween composited C60-Fe3O4-DOX microbubbles, PLA-Tween composited C60-Fe3O4-NET microbubbles and PLA-Tween composited C60-Fe3O4-WF microbubbles were obtained, respectively. The average particle size of PLA-Tween composited drug-carrying C60-Fe3O4 microbubbles was 446.4 nm, the microbubble size was uniform, and the Zeta potential was -40.5 mV which showed a good stability. The loading rates of DOX, NET and WF in PLA-Tween composited drug-carrying C60-Fe3O4 microbubbles were 5.58%, 8.15% and 3.37%, respectively. PLA-Tween composited C60-Fe3O4-DOX microbubbles could inhibit the breast cancer MDA-MB-231 cells and normal mouse fibroblast 3T3 cells, the inhibition rates were respectively 53.4% and 18.6%, which significantly reduced the toxicity of free DOX drug on the normal cells (62.2%). PLA-Tween composited C60-Fe3O4-NET microbubbles had a inhibitory effect on the growth of Staphylococcus aureus and Escherichia coli, and the inhibitory effect on Escherichia coli was better. PLA-Tween composited C60-Fe3O4-WF microbubbles could inhibit the formation of thrombus, and PT, TT and APTT were significantly prolonged. PLA-Tween composited C60-Fe3O4 microbubbles had a developing effect on the kidney, bladder and abdominal aorta of rabbit. Under the action of external magnetic field, the ultrasonic imaging effect of composite microbubbles was significantly enhanced.

Organocatalytic Asymmetric Dearomatization of 3-Nitroindoles and 3-Nitrobenzothiophenes via Thiol-Triggered Diastereo- and Enantioselective Double Michael Addition Reaction.

Organocatalytic asymmetric dearomatization of 3-nitroindoles and 3-nitrobenzothiophenes by reaction with ethyl 4-mercapto-2-butenoate has been developed. A range of chiral tetrahydrothiopheneindolines and tetrahydrothiophenebenzothiophenes bearing three contiguous stereocenters are obtained in high yields with good diastereoselectivities and excellent enantioselectivities. This is the first example of thiol-triggered catalytic asymmetric dearomatization of 3-nitroindoles and 3-nitrobenzothiophenes.

Pyrrole-Hemoglobin Adducts, a More Feasible Potential Biomarker of Pyrrolizidine Alkaloid Exposure.

Pyrrolizidine alkaloids (PAs) are naturally occurring phytotoxins widely distributed in about 3% of flowering plants. The formation of PA-derived pyrrole-protein adducts is considered as a primary trigger initiating PA-induced hepatotoxicity. The present study aims to (i) further validate our previous established derivatization method using acidified ethanolic AgNO3 for the analysis of pyrrole-protein adducts and (ii) apply this method to characterize the binding tendency, dose-response, and elimination kinetics of pyrrole-protein adducts in blood samples. Two pyrrole-amino acid conjugates, (±)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5 H-pyrrolizine (DHP)-cysteine (7-cysteine-DHP) and 9-histidine-DHP, were synthesized and used to demonstrate that acidified ethanolic AgNO3 derivatization can cleave both S-linkage and N-linkage of pyrrole-protein adducts. Subsequently, using precolumn AgNO3 derivatization followed by ultra-high-pressure liquid chromatography/mass spectrometry analysis, we quantified pyrrole-protein adducts in monocrotaline-treated rat blood protein fractions, including hemoglobin (Hb), plasma, albumin, and plasma residual protein fractions, and found that the amount of pyrrole-Hb adducts was significantly higher than that in all plasma fractions. Moreover, elimination half-life of pyrrole-Hb adducts was also significantly longer than pyrrole-protein adducts in plasma fractions (12.08 vs 2.54-2.93 days). In addition, we also tested blood samples obtained from five PA-induced liver injury patients and found that the amount of pyrrole-protein adducts in blood cells was also remarkably higher than that in plasma. In conclusion, our findings for the first time confirmed that the AgNO3 derivatization method could be used to measure both S- and N-linked pyrrole-protein adducts and also suggested that pyrrole-Hb adducts with remarkably higher level and longer life span could be a better biomarker of PA exposure.

Organocatalyzed Asymmetric Dearomative Aza-Michael/Michael Addition Cascade of 2-Nitrobenzofurans and 2-Nitrobenzothiophenes with 2-Aminochalcones.

An organocatalyzed dearomative aza-Michael/Michael addition cascade of 2-nitrobenzofurans and 2-nitrobenzothiophenes with 2-aminochalcones has been developed, opening a new channel to access a series of optically active tetrahydrobenzofuro[3,2- b]quinolines and tetrahydrobenzo[4,5]thieno[3,2- b]quinolines bearing three contiguous stereocenters with excellent diastereo- and enantioselectivities (all cases >20:1 dr, up to 99% ee). This study features the first asymmetric dearomative cascade reaction of 2-nitrobenzofurans and 2-nitrobenzothiophenes beginning with aza-Michael addition. The potential applications of the methodology were demonstrated by the preparative-scale experiment and the versatile transformations of the products.

A Maitake (Grifola frondosa) polysaccharide ameliorates Alzheimer's disease-like pathology and cognitive impairments by enhancing microglial amyloid-ß clearance.

Alzheimer's disease (AD) is characterized by the deposition of amyloid-ß (Aß) plaques, neuronal loss and neurofibrillary tangles. In addition, neuroinflammatory processes are thought to contribute to AD pathophysiology. Maitake (Grifola frondosa), an edible/medicinal mushroom, exhibits high nutritional value and contains a great amount of health-beneficial, bioactive compounds. It has been reported that proteo-ß-glucan, a polysaccharide derived from Maitake (PGM), possesses strong immunomodulatory activities. However, whether PGM is responsible for the immunomodulatory and neuroprotection effects on APPswe/PS1ΔE9 (APP/PS1) transgenic mice, a widely used animal model of AD, remains unclear. In the present study, the results demonstrated that PGM could improve learning and memory impairment, attenuate neuron loss and histopathological abnormalities in APP/PS1 mice. In addition, PGM treatment could activate microglia and astrocytes and promote microglial recruitment to the Aß plaques. Also, PGM could enhance Aß phagocytosis, and thereby alleviate Aß burden and the pathological changes in the cortex and hippocampus in APP/PS1 mice. Moreover, PGM showed no significant effect on mice body weight. In conclusion, these findings indicated that administration of PGM could improve memory impairment via immunomodulatory action, and dietary supplementation with PGM may provide potential benefits on brain aging related memory dysfunction.

Competitive McLafferty-type rearrangements of sodium adduct of anti-2,3-dihydroxy-1-phenylpentane-1,4-dione compounds in tandem mass spectrometry.

Sodium adducts of anti-2,3-dihydroxy-1-phenylpentane-1,4-dione compounds with different substituents were studied by collision-induced dissociation. McLafferty-type rearrangements preceding fragmentation were found as their main fragmentation pathway. Coordination of sodium cation to the oxygen functions may either lead to formation of a five-membered or a six-membered ring. Two McLafferty-type rearrangement product ions exhibiting a mass difference of 2 u indicated that two competitive McLafferty-type rearrangements through a six-membered ring coordination occurred. Relative abundances of the corresponding product ions were studied by energy-resolved collision-induced dissociation experiments and density functional theory calculations. Furthermore, the influence of different substituents was probed.

Simultaneous quantification of imatinib and its main metabolite N-demethyl-imatinib in human plasma by liquid chromatography-tandem mass spectrometry and its application to therapeutic drug monitoring in patients with gastrointestinal stromal tumor.

The aim of this study was to improve and validate a more stable and less time-consuming method based on liquid chromatography and tandem mass spectrometry (LC- MS/MS) for the quantitative measurement of imatinib and its metabolite N-demethyl-imatinib (NDI) in human plasma. Separation of analytes was performed on a Waters XTerra RP18 column (50 × 2.1 mm i.d., 3.5 µm) with a mobile phase consisting of methanol-acetonitrile-water (65:20:15, v/v/v) with 0.05% formic acid at a flow-rate of 0.2 mL/min. The Quattro MicroTM triple quadruple mass spectrometer was operated in the multiple-reaction-monitoring mode via positive electrospray ionization interface using the transitions m/z 494.0 → 394.0 for imatinib, m/z 479.6 → 394.0 for NDI and m/z 488.2 → 394.0 for IS. The method was linear over 0.01-10 µg/mL for imatinib and NDI. The intra- and inter-day precisions were all <15% in terms of relative standard deviation, and the accuracy was within ±15% in terms of relative error for both imatinib and NDI. The lower limit of quantification was identifiable and reproducible at 10 ng/mL. The method was sensitive, specific and less time-consuming and it was successfully applied in gastrointestinal stromal tumor patients treated with imatinib.

pDHS-SVM: A prediction method for plant DNase I hypersensitive sites based on support vector machine.

DNase I hypersensitive sites (DHSs) are accessible chromatin regions hypersensitive to cleavages by DNase I endonucleases. DHSs are indicative of cis-regulatory DNA elements (CREs), all of which play important roles in global gene expression regulation. It is helpful for discovering CREs by recognition of DHSs in genome. To accelerate the investigation, it is an important complement to develop cost-effective computational methods to identify DHSs. However, there is a lack of tools used for identifying DHSs in plant genome. Here we presented pDHS-SVM, a computational predictor to identify plant DHSs. To integrate the global sequence-order information and local DNA properties, reverse complement kmer and dinucleotide-based auto covariance of DNA sequences were applied to construct the feature space. In this work, fifteen physical-chemical properties of dinucleotides were used and Support Vector Machine (SVM) was employed. To further improve the performance of the predictor and extract an optimized subset of nucleotide physical-chemical properties positive for the DHSs, a heuristic nucleotide physical-chemical property selection algorithm was introduced. With the optimized subset of properties, experimental results of Arabidopsis thaliana and rice (Oryza sativa) showed that pDHS-SVM could achieve accuracies up to 87.00%, and 85.79%, respectively. The results indicated the effectiveness of proposed method for predicting DHSs. Furthermore, pDHS-SVM could provide a helpful complement for predicting CREs in plant genome. Our implementation of the novel proposed method pDHS-SVM is freely available as source code, at https://github.com/shanxinzhang/pDHS-SVM.

Associations of MDR1, TBXA2R, PLA2G7, and PEAR1 genetic polymorphisms with the platelet activity in Chinese ischemic stroke patients receiving aspirin therapy.

AIM: Aspirin resistance has an incidence of 5%-65% in patients with ischemic stroke, who receive the standard dose of aspirin, but the platelet function is inadequately inhibited, thereby leading to thrombotic events. Numerous evidence shows that thromboxane A2 receptor (TXA2 receptor, encoded by TBXA2R), lipoprotein-associated phospholipase A2 (Lp-PLA2, encoded by PLA2G7) and platelet endothelial aggregation receptor-1 (PEAR1, encoded by PEAR1) are crucial in regulating platelet activation, and P-glycoprotein (P-gp, encoded by MDR1) influences the absorption of aspirin in the intestine. In this study we examined the correlation between MDR1, TBXA2R, PLA2G7, PEAR1 genetic polymorphisms and platelet activity in Chinese ischemic stroke patients receiving aspirin therapy. METHODS: A total of 283 ischemic stroke patients receiving 100 mg aspirin for 7 d were genotyped for polymorphisms in MDR1 C3435T, TBXA2R (rs1131882), PLA2G7 (rs1051931, rs7756935), and PEAR1 (rs12566888, rs12041331). The platelet aggregation response was measured using an automatic platelet aggregation analyzer and a commercially available TXB2 ELISA kit. RESULTS: Thirty-three patients (11.66%) were insensitive to aspirin treatment. MDR1 3435TT genotype carriers, whose arachidonic acid (AA) or adenosine diphosphate (ADP)-induced platelet aggregation was lower than that of CC+CT genotype carriers, were less likely to suffer from aspirin resistance (odds ratio=0.421, 95% CI: 0.233-0.759). The TBXA2R rs1131882 CC genotype, which was found more frequently in the aspirin-insensitive group (81.8% vs 62.4%) than in the sensitive group, was identified as a risk factor for aspirin resistance (odds ratio=2.712, 95% CI: 1.080-6.810) with a higher level of AA-induced platelet aggregation. Due to the combined effects of PLA2G7 rs1051931 and rs7756935, carriers of the AA-CC haplotype had a higher level of ADP-induced platelet aggregation, and were at considerably higher risk of aspirin resistance than noncarriers (odds ratio=8.233, 95% CI: 1.590-42.638). CONCLUSION: A considerable portion (11.66%) of Chinese ischemic stroke patients are insensitive to aspirin treatment, which may be correlated with the MDR1 C3435T, TBXA2R (rs1131882), and PLA2G7 (rs1051931-rs7756935) polymorphisms.

Effect of Ginkgo Biloba Extract on the Pharmacokinetics and Metabolism of Clopidogrel in Rats.

Ginkgo biloba extract (GBE), a traditional herbal product used worldwide as both medicine and supplement, is often supplied with clopidogrel for the treatment of cerebrovascular diseases. The aim of the current study was to explore the effect of GBE on the metabolism and pharmacokinetics of clopidogrel. The in vitro study using rat liver microsomes revealed that GBE significantly induced the conversion of clopidogrel into its active metabolite. The effect of GBE on the pharmacokinetics of clopidogrel was also investigated in vivo. Compared to rats without GBE pretreatment, administration of 4 mg/kg, 20 mg/kg, and 100 mg/kg of GBE significantly decreased the Cmax and the AUC0-∞ of clopidogrel in a dose-dependent manner. As expected, pretreatment of high dose GBE significantly increased the Cmax and AUC0-∞ of the clopidogrel active metabolite. However, no marked change was observed following medium and low dose of GBE, suggesting that the biotransformation of clopidogrel was altered differently by high dose of GBE. Our study suggested that the awareness of the potential herb-drug interactions between GBE and clopidogrel should be increased in clinical practice. Copyright © 2016 John Wiley & Sons, Ltd.

Mechanistic understanding of the effect of Dengzhan Shengmai capsule on the pharmacokinetics of clopidogrel in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: The Dengzhan Shengmai capsule (DZSM) is known in China for its remarkable curative effect as a treatment of cardiovascular diseases, such as coronary heart disease and ischemic stroke. DZSM is a Chinese herbal compound preparation that consists of four ingredients, including Erigeron breviscapus (Vaniot) Hand.-Mazz., Panax ginseng C.A. Mey, Ophiopogon japonicas (Thunb.) Ker-Gawl. and Schisandra chinensis (Turcz.) Baill., and was indexed in the Chinese Pharmacopoeia 2010. DZSM and clopidogrel are often co-prescribed in the clinic to prevent the recurrence of stroke or other cardiovascular and cerebrovascular diseases. However, the effect of DZSM on the pharmacokinetics of clopidogrel remains unclear. AIM OF THE STUDY: The purpose of the study is to explore the pharmacokinetics and potential interaction between DZSM and clopidogrel and the underlying mechanism. MATERIALS AND METHODS: Rats were used to investigate the effect of DZSM on the pharmacokinetics of clopidogrel and its active metabolite in vivo. The plasma concentrations were simultaneously determined using LC-MS/MS. The effects of DZSM on the P-gp-mediated efflux transport and CYP450-mediated metabolism of clopidogrel were investigated using MDCKII-MDR1 cells and rat liver microsomes, respectively. RESULTS: After pretreatment with DZSM, the Cmax and AUC0-∞ of clopidogrel increased from 0.4±0.1 to 1.7±0.6ng/mL and 0.9±0.4 to 2.0±0.2ng/mLh, respectively. The Cmax and AUC0-∞ of the derivatized active metabolite of clopidogrel decreased from 8.2±1.2 to 2.8±0.5ng/mL and 18.2±5.6 to 6.4±3.7ngh/mL, respectively. In MDCKII-MDR1 cells, the P-gp-mediated efflux transport of clopidogrel was significantly inhibited by the DZSM extract. In rat liver microsomes, DZSM inhibited clopidogrel metabolism with an IC50 of 0.02mg/mL. CONCLUSIONS: DZSM significantly affects the pharmacokinetics of clopidogrel and its active metabolite by inhibiting the P-gp-mediated efflux transport and CYP450-mediated metabolism of clopidogrel. Thus, caution is needed when DZSM is co-administered with clopidogrel in the clinic because the interaction of these drugs may result in altered plasma concentrations of clopidogrel and its active metabolite.